Lymphocyte Doubling Time As A Key Prognostic Factor To Predict Time To First Treatment In Early-Stage Chronic Lymphocytic Leukemia

被引:9
作者
Morabito, Fortunato [1 ,2 ]
Tripepi, Giovanni [3 ]
Moia, Riccardo [4 ]
Recchia, Anna Grazia [1 ]
Boggione, Paola [4 ]
Mauro, Francesca Romana [5 ]
Bossio, Sabrina [1 ]
D'Arrigo, Graziella [3 ]
Martino, Enrica Antonia [6 ]
Vigna, Ernesto [6 ]
Storino, Francesca [1 ]
Fronza, Gilberto [7 ]
Di Raimondo, Francesco [8 ]
Rossi, Davide [9 ]
Condoluci, Adalgisa [9 ]
Colombo, Monica [10 ]
Fais, Franco [10 ,11 ]
Fabris, Sonia [12 ]
Foa, Robin [5 ]
Cutrona, Giovanna [10 ]
Gentile, Massimo [6 ]
Montserrat, Emili [13 ]
Gaidano, Gianluca [4 ]
Ferrarini, Manlio [11 ]
Neri, Antonino [12 ,14 ]
机构
[1] Azienda Osped AO Cosenza, Biotechnol Res Unit, Dept Oncohematol, Cosenza, Italy
[2] Augusta Victoria Hosp, Dept Hematol & Bone Marrow Transplant Unit, Jerusalem, Israel
[3] CNR, Res Unit Reggio Calabria, Ist Fisiol Clin CNR IFC, Reggio Di Calabria, Italy
[4] Univ Piemonte Orientale, Dept Translat Med, Div Hematol, Novara, Italy
[5] Sapienza Univ, Dept Translat & Precis Med, Hematol, Rome, Italy
[6] Dept Oncohematol AO Cosenza, Hematol Unit AO Cosenza, Cosenza, Italy
[7] IRCCS Osped Policlin San Martino, Mutagenesis & Canc Prevent Unit, Genoa, Italy
[8] Univ Catania, Dept Surg & Med Specialties, Div Hematol, Policlin, Catania, Italy
[9] Oncol Inst Southern Switzerland, Hematol, Bellinzona, Switzerland
[10] IRCCS Osped Policlin San Martino, Mol Pathol Unit, Genoa, Italy
[11] Univ Genoa, Dept Expt Med, Genoa, Italy
[12] Osped Maggiore Policlin, Hematol Unit, Fdn IRCCS Ca Granda, Milan, Italy
[13] Inst Invest Biomed August Pi & Sunyer IDIBAPS, Hosp Clin, Dept Hematol, Barcelona, Spain
[14] Univ Milan, Dept Oncol & Hematooncol, Milan, Italy
来源
FRONTIERS IN ONCOLOGY | 2021年 / 11卷
基金
欧洲研究理事会; 瑞士国家科学基金会;
关键词
CLL; prognosis; lymphocyte doubling time; TTFT; early stage; COMPUTED-TOMOGRAPHY SCAN; BINET STAGE; PROSPECTIVE VALIDATION; EXTERNAL VALIDATION; FREE SURVIVAL; RISK SCORE; PROGRESSION; INDEX; DIAGNOSIS; METHYLATION;
D O I
10.3389/fonc.2021.684621
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
The prognostic role of lymphocyte doubling time (LDT) in chronic lymphocytic leukemia (CLL) was recognized more than three decades ago when the neoplastic clone's biology was almost unknown. LDT was defined as the time needed for the peripheral blood lymphocyte count to double the of the initial observed value. Herein, the LDT prognostic value for time to first treatment (TTFT) was explored in our prospective O-CLL cohort and validated in in two additional CLL cohorts. Specifically, newly diagnosed Binet stage A CLL patients from 40 Italian Institutions, representative of the whole country, were prospectively enrolled into the O-CLL1-GISL protocol ( identifier: NCT00917540). Two independent cohorts of newly diagnosed CLL patients recruited respectively at the Division of Hematology in Novara, Italy, and at the Hospital Clinic in Barcelona, Spain, were utilized as validation cohorts. In the training cohort, TTFT of patients with LDT > 12 months was significantly longer related to those with a shorter LDT. At Cox multivariate regression model, LDT <= 12 months maintained a significant independent relationship with shorter TTFT along with IGHV unmutated (IGHVunmut) status, 11q and 17p deletions, elevated beta 2M, Rai stage I-II, and NOTCH1 mutations. Based on these statistics, two regression models were constructed including the same prognostic factors with or without the LDT. The model with the LTD provided a significantly better data fitting (chi(2) = 8.25, P=0.0041). The risk prediction developed including LDT had better prognostic accuracy than those without LDT. Moreover, the Harrell'C index for the scores including LDT were higher than those without LDT, although the accepted 0.70 threshold exceeded in both cases. These findings were also confirmed when the same analysis was carried out according to TTFT's explained variation. When data were further analyzed based on the combination between LDT and IGHV mutational status in the training and validation cohorts, IGHVunmut and LDT > 12months group showed a predominant prognostic role over IGHVmut LTD & LE; 12 months (P=0.006) in the O-CLL validation cohort. However, this predominance was of borden-line significance (P=0.06) in the Barcelona group, while the significant prognostic impact was definitely lost in the Novara group. Overall, in this study, we demonstrated that LDT could be re-utilized together with the more sophisticated prognostic factors to manage the follow-up plans for Binet stage A CLL patients.
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页数:12
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共 68 条
[1]   NEW LOOK AT STATISTICAL-MODEL IDENTIFICATION [J].
AKAIKE, H .
IEEE TRANSACTIONS ON AUTOMATIC CONTROL, 1974, AC19 (06) :716-723
[2]   Elevated Lactate Dehydrogenase Has Prognostic Relevance in Treatment-Naive Patients Affected by Chronic Lymphocytic Leukemia with Trisomy 12 [J].
Autore, Francesco ;
Strati, Paolo ;
Innocenti, Idanna ;
Corrente, Francesco ;
Trentin, Livio ;
Cortelezzi, Agostino ;
Visco, Carlo ;
Coscia, Marta ;
Cuneo, Antonio ;
Gozzetti, Alessandro ;
Mauro, Francesca Romana ;
Frustaci, Anna Maria ;
Gentile, Massimo ;
Morabito, Fortunato ;
Molica, Stefano ;
Falcucci, Paolo ;
D'Arena, Giovanni ;
Murru, Roberta ;
Vincelli, Donatella ;
Efremov, Dimitar G. ;
Ferretti, Antonietta ;
Rigolin, Gian Matteo ;
Vitale, Candida ;
Tisi, Maria Chiara ;
Reda, Gianluigi ;
Visentin, Andrea ;
Sica, Simona ;
Foa, Robin ;
Ferrajoli, Alessandra ;
Laurenti, Luca .
CANCERS, 2019, 11 (07)
[3]   Lymphocyte doubling time in chronic lymphocytic leukemia modern era: a real-life study in 848 unselected patients [J].
Baumann, Tycho ;
Moia, Riccardo ;
Gaidano, Gianluca ;
Delgado, Julio ;
Condoluci, Adalgisa ;
Villamor, Neus ;
Payedimarri, Anil Babu ;
Costa, Dolors ;
Patriarca, Andrea ;
Jimenez-Vicente, Carlos ;
Rossi, Davide ;
Montserrat, Emili .
LEUKEMIA, 2021, 35 (08) :2325-2331
[4]   Chronic lymphocytic leukaemia: from genetics to treatment [J].
Bosch, Francesc ;
Dalla-Favera, Riccardo .
NATURE REVIEWS CLINICAL ONCOLOGY, 2019, 16 (11) :684-701
[5]   A laboratory-based scoring system predicts early treatment in Rai 0 chronic lymphocytic leukemia [J].
Cohen, Jared A. ;
Rossi, Francesca Maria ;
Zucchetto, Antonella ;
Bomben, Riccardo ;
Terzi-di-Bergamo, Lodovico ;
Rabe, Kari G. ;
Degan, Massimo ;
Steffan, Agostino ;
Polesel, Jerry ;
Santinelli, Enrico ;
Innocenti, Idanna ;
Cutrona, Giovanna ;
D'Arena, Giovanni ;
Pozzato, Gabriele ;
Zaja, Francesco ;
Chiarenza, Annalisa ;
Rossi, Davide ;
Di Raimondo, Francesco ;
Laurenti, Luca ;
Gentile, Massimo ;
Morabito, Fortunato ;
Neri, Antonino ;
Ferrarini, Manlio ;
Fegan, Christopher D. ;
Pepper, Christopher J. ;
Del Poeta, Giovanni ;
Parikh, Sameer A. ;
Kay, Neil E. ;
Gattei, Valter .
HAEMATOLOGICA, 2020, 105 (06) :1613-1620
[6]   International prognostic score for asymptomatic early-stage chronic lymphocytic leukemia [J].
Condoluci, Adalgisa ;
di Bergamo, Lodovico Terzi ;
Langerbeins, Petra ;
Hoechstetter, Manuela A. ;
Herling, Carmen D. ;
De Paoli, Lorenzo ;
Delgado, Julio ;
Rabe, Kari G. ;
Gentile, Massimo ;
Doubek, Michael ;
Mauro, Francesca R. ;
Chiodin, Giorgia ;
Mattsson, Mattias ;
Bahlo, Jasmin ;
Cutrona, Giovanna ;
Kotaskova, Jana ;
Deambrogi, Clara ;
Smedby, Karin E. ;
Spina, Valeria ;
Bruscaggin, Alessio ;
Wu, Wei ;
Moia, Riccardo ;
Bianchi, Elena ;
Gerber, Bernhard ;
Zucca, Emanuele ;
Gillessen, Silke ;
Ghielmini, Michele ;
Cavalli, Franco ;
Stussi, Georg ;
Hess, Mark A. ;
Baumann, Tycho S. ;
Neri, Antonino ;
Ferrarini, Manlio ;
Rosenquist, Richard ;
Forconi, Francesco ;
Foa, Robin ;
Pospisilova, Sarka ;
Morabito, Fortunato ;
Stilgenbauer, Stephan ;
Doehner, Hartmut ;
Parikh, Sameer A. ;
Wierda, William G. ;
Montserrat, Emili ;
Gaidano, Gianluca ;
Hallek, Michael ;
Rossi, Davide .
BLOOD, 2020, 135 (21) :1859-1869
[7]   Quantifying the added value of new biomarkers: how and how not [J].
Nancy R. Cook .
Diagnostic and Prognostic Research, 2 (1)
[8]   Clonal heterogeneity in chronic lymphocytic leukemia cells: superior response to surface IgM cross-linking in CD38, ZAP-70-positive cells [J].
Cutrona, Giovanna ;
Colombo, Monica ;
Matis, Serena ;
Fabbi, Marina ;
Spriano, Mauro ;
Callea, Vincenzo ;
Vigna, Ernesto ;
Gentile, Massimo ;
Zupo, Simonetta ;
Chiorazzi, Nicholas ;
Morabito, Fortunato ;
Ferrarini, Manlio .
HAEMATOLOGICA, 2008, 93 (03) :413-422
[9]   Statistical methods to assess the prognostic value of risk prediction rules in clinical research [J].
D'Arrigo, Graziella ;
Gori, Mercedes ;
Pitino, Annalisa ;
Torino, Claudia ;
Roumeliotis, Stefanos ;
Tripepi, Giovanni .
AGING CLINICAL AND EXPERIMENTAL RESEARCH, 2021, 33 (02) :279-283
[10]   Molecular and transcriptional characterization of 17p loss in B-cell chronic lymphocytic leukemia [J].
Fabris, Sonia ;
Mosca, Laura ;
Todoerti, Katia ;
Cutrona, Giovanna ;
Lionetti, Marta ;
Intini, Daniela ;
Matis, Serena ;
Colombo, Monica ;
Agnelli, Luca ;
Gentile, Massimo ;
Spriano, Mauro ;
Callea, Vincenzo ;
Festini, Gianluca ;
Molica, Stefano ;
Deliliers, Giorgio Lambertenghi ;
Morabito, Fortunato ;
Ferrarini, Manlio ;
Neri, Antonino .
GENES CHROMOSOMES & CANCER, 2008, 47 (09) :781-793