PURPOSE: Randomized trials established the superiority of ibrutinib-based therapy over chemoimmunotherapy in chronic lymphocytic leukemia. Durability of progression-free survival (PFS) with ibrutinib can vary by patient subgroup. Clinical tools for prognostication and risk-stratification are needed. PATIENTS AND METHODS: Patients treated with ibrutinib in phase II and III trials provided the discovery data set and were subdivided into discovery and internal validation cohorts. An external validation cohort included 84 patients enrolled in our investigator-initiated phase II trial. Univariable analysis of 18 pretreatment parameters was performed using PFS and overall survival (OS) end-points. Multivariable analysis and machine-learning algorithms identified four factors for a prognostic model that was validated in internal and external cohorts. RESULTS: Factors independently associated with inferior PFS and OS were as follows: TP53 aberration, prior treatment, β-2 microglobulin ≥ 5 mg/L, and lactate dehydrogenase > 250 U/L. Each of these four factors contributed one point to a prognostic model that stratified patients into three risk groups: three to four points, high risk; two points, intermediate risk; zero to one point, low risk. The 3-year PFS rates for all 804 patients combined were 47%, 74%, and 87% for the high-, the intermediate-, and the low-risk group, respectively (P < .0001). The 3-year OS rates were 63%, 83%, and 93%, respectively (P < .0001). The model remained significant when applied to treatment-naïve and relapsed/refractory cohorts individually. For 84 patients in the external cohort, BTK and PLCG2 mutations were tested cross-sectionally and at progression. The cumulative incidences of mutations were strongly correlated with the model. In the external cohort, Richter's transformation occurred in 17% of the high-risk group, and in no patient in the low-risk group. CONCLUSION: Patients at increased risk of ibrutinib failure can be identified at treatment initiation and considered for clinical trials.
PURPOSE: Randomized trials established the superiority of ibrutinib-based therapy over chemoimmunotherapy in chronic lymphocytic leukemia. Durability of progression-free survival (PFS) with ibrutinib can vary by patient subgroup. Clinical tools for prognostication and risk-stratification are needed. PATIENTS AND METHODS: Patients treated with ibrutinib in phase II and III trials provided the discovery data set and were subdivided into discovery and internal validation cohorts. An external validation cohort included 84 patients enrolled in our investigator-initiated phase II trial. Univariable analysis of 18 pretreatment parameters was performed using PFS and overall survival (OS) end-points. Multivariable analysis and machine-learning algorithms identified four factors for a prognostic model that was validated in internal and external cohorts. RESULTS: Factors independently associated with inferior PFS and OS were as follows: TP53 aberration, prior treatment, β-2 microglobulin ≥ 5 mg/L, and lactate dehydrogenase > 250 U/L. Each of these four factors contributed one point to a prognostic model that stratified patients into three risk groups: three to four points, high risk; two points, intermediate risk; zero to one point, low risk. The 3-year PFS rates for all 804 patients combined were 47%, 74%, and 87% for the high-, the intermediate-, and the low-risk group, respectively (P < .0001). The 3-year OS rates were 63%, 83%, and 93%, respectively (P < .0001). The model remained significant when applied to treatment-naïve and relapsed/refractory cohorts individually. For 84 patients in the external cohort, BTK and PLCG2 mutations were tested cross-sectionally and at progression. The cumulative incidences of mutations were strongly correlated with the model. In the external cohort, Richter's transformation occurred in 17% of the high-risk group, and in no patient in the low-risk group. CONCLUSION: Patients at increased risk of ibrutinib failure can be identified at treatment initiation and considered for clinical trials.
Authors: Andrew J Souers; Joel D Leverson; Erwin R Boghaert; Scott L Ackler; Nathaniel D Catron; Jun Chen; Brian D Dayton; Hong Ding; Sari H Enschede; Wayne J Fairbrother; David C S Huang; Sarah G Hymowitz; Sha Jin; Seong Lin Khaw; Peter J Kovar; Lloyd T Lam; Jackie Lee; Heather L Maecker; Kennan C Marsh; Kylie D Mason; Michael J Mitten; Paul M Nimmer; Anatol Oleksijew; Chang H Park; Cheol-Min Park; Darren C Phillips; Andrew W Roberts; Deepak Sampath; John F Seymour; Morey L Smith; Gerard M Sullivan; Stephen K Tahir; Chris Tse; Michael D Wendt; Yu Xiao; John C Xue; Haichao Zhang; Rod A Humerickhouse; Saul H Rosenberg; Steven W Elmore Journal: Nat Med Date: 2013-01-06 Impact factor: 53.440
Authors: Carol Moreno; Richard Greil; Fatih Demirkan; Alessandra Tedeschi; Bertrand Anz; Loree Larratt; Martin Simkovic; Olga Samoilova; Jan Novak; Dina Ben-Yehuda; Vladimir Strugov; Devinder Gill; John G Gribben; Emily Hsu; Chih-Jian Lih; Cathy Zhou; Fong Clow; Danelle F James; Lori Styles; Ian W Flinn Journal: Lancet Oncol Date: 2018-12-03 Impact factor: 41.316
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Authors: Philip A Thompson; Susan M O'Brien; William G Wierda; Alessandra Ferrajoli; Francesco Stingo; Susan C Smith; Jan A Burger; Zeev Estrov; Nitin Jain; Hagop M Kantarjian; Michael J Keating Journal: Cancer Date: 2015-07-20 Impact factor: 6.860
Authors: A R Mato; B T Hill; N Lamanna; P M Barr; C S Ujjani; D M Brander; C Howlett; A P Skarbnik; B D Cheson; C S Zent; J J Pu; P Kiselev; K Foon; J Lenhart; S Henick Bachow; A M Winter; A-L Cruz; D F Claxton; A Goy; C Daniel; K Isaac; K H Kennard; C Timlin; M Fanning; L Gashonia; M Yacur; J Svoboda; S J Schuster; C Nabhan Journal: Ann Oncol Date: 2017-05-01 Impact factor: 32.976
Authors: Panagiotis Baliakas; Sabine Jeromin; Michalis Iskas; Anna Puiggros; Karla Plevova; Florence Nguyen-Khac; Zadie Davis; Gian Matteo Rigolin; Andrea Visentin; Aliki Xochelli; Julio Delgado; Fanny Baran-Marszak; Evangelia Stalika; Pau Abrisqueta; Kristina Durechova; George Papaioannou; Virginie Eclache; Maria Dimou; Theodoros Iliakis; Rosa Collado; Michael Doubek; M Jose Calasanz; Neus Ruiz-Xiville; Carolina Moreno; Marie Jarosova; Alexander C Leeksma; Panayiotis Panayiotidis; Helena Podgornik; Florence Cymbalista; Achilles Anagnostopoulos; Livio Trentin; Niki Stavroyianni; Fred Davi; Paolo Ghia; Arnon P Kater; Antonio Cuneo; Sarka Pospisilova; Blanca Espinet; Anastasia Athanasiadou; David Oscier; Claudia Haferlach; Kostas Stamatopoulos Journal: Blood Date: 2019-01-02 Impact factor: 22.113
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Authors: John C Byrd; Richard R Furman; Steven E Coutre; Ian W Flinn; Jan A Burger; Kristie A Blum; Barbara Grant; Jeff P Sharman; Morton Coleman; William G Wierda; Jeffrey A Jones; Weiqiang Zhao; Nyla A Heerema; Amy J Johnson; Juthamas Sukbuntherng; Betty Y Chang; Fong Clow; Eric Hedrick; Joseph J Buggy; Danelle F James; Susan O'Brien Journal: N Engl J Med Date: 2013-06-19 Impact factor: 91.245
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