TY - JOUR
T1 - Prognostic risk score for patients with relapsed or refractory chronic lymphocytic leukaemia treated with targeted therapies or chemoimmunotherapy
T2 - a retrospective, pooled cohort study with external validations
AU - Soumerai, Jacob D.
AU - Ni, Ai
AU - Darif, Mohamed
AU - Londhe, Anil
AU - Xing, Guan
AU - Mun, Yong
AU - Kay, Neil E.
AU - Shanafelt, Tait D.
AU - Rabe, Kari G.
AU - Byrd, John C.
AU - Chanan-Khan, Asher A.
AU - Furman, Richard R.
AU - Hillmen, Peter
AU - Jones, Jeffrey
AU - Seymour, John F.
AU - Sharman, Jeffrey P.
AU - Ferrante, Lucille
AU - Mobasher, Mehrdad
AU - Stark, Thomas
AU - Reddy, Vijay
AU - Dreiling, Lyndah K.
AU - Bhargava, Pankaj
AU - Howes, Angela
AU - James, Danelle F.
AU - Zelenetz, Andrew D.
N1 - Funding Information:
JDS receives research support from Genentech/Roche, BeiGene, and TG Therapeutics, and consultancy from Verastem. MD reports employment from Janssen. AL reports employment and stock ownership from Janssen. GX reports employment from Gilead. YM reports employement from Genentech. NEK reports research support from Acerta, Pharmacyclics, MEI Pharma, and Genentech. TDS reports research support from Pharmacyclics, Janssen, Genentech, GlaxoSmithKline, Celgene, AbbVie, Cephalon, and Hospira. RRF reports consultancies from Abbvie, Acerta, AstraZeneca, Genentech, Janssen, Loxo Oncology, Pharmacyclics, Sunesis, TG Therapeutics, Verastem, and Gilead, and serves on data safety monitoring board for Incyte. PH reports research support and consultancies from Janssen, Pharmacyclics, Gilead, AbbVie, and Roche. JJ reports employment from Celgene and consultancies from Abbvie and Gilead. JFS reports research support from AbbVie, Celgene, Janssen, and Roche, consultancies from AbbVie, Acerta, Celgene, Janssen, Roche, and Takeda, and travel support and speaker fees from Abbvie, Celgene, and Genentech/Roche. JPS reports consultancies and research support from Gilead and TG Therapeutics. LF reports employment and stock ownership from Janssen. MM reports employment and stock ownership from Genentech/Roche. TS reports employment and stock ownership from Janssen and Genentech/Roche. VR reports employment from Pharmacyclics. LKD and PB report employment from Gilead. AH reports employment from Janssen. DFJ reports research funding from Acerta, and employment and stock ownership from AbbVie/Pharmacyclics. ADZ reports consultancies from Genentech, Celgene, Janssen, Amgen, Novartis, Adaptive Biotechnology, MEI Pharma, Roche, AstraZeneca, MorphoSys, Abbvie, and Beigene Pharmaceuticals, research support from Gilead, MEI Pharma, and Roche, and data safety monitoring committee chairmanship from BeiGene. AN, KGR, JCB, and AAC-K declare no competing interests.
Funding Information:
This study was funded by the Lymphoma Research Foundation under Clinical Investigator Career Development Award ( 549904 ) and Lymphoma Clinical Research Mentoring Program (498061), the Lymphoma Research Fund (Andrew D. Zelenetz), and the National Institutes of Health/National Cancer Institute Core Grant ( P30CA008748 ).
Publisher Copyright:
© 2019 Elsevier Ltd
PY - 2019/7
Y1 - 2019/7
N2 - Background: Clinically validated prognostic models for overall survival do not exist for patients with relapsed or refractory chronic lymphocytic leukaemia (CLL) who are on targeted therapies. We aimed to create a prognostic model to identify high-risk individuals who do not achieve a good outcome with available targeted therapies. Methods: In this retrospective, pooled cohort study, 2475 patients with CLL treated between June 22, 2012, and Sept 23, 2015, in six randomised trials of ibrutinib, idelalisib, and venetoclax, or at the Mayo Clinic CLL Database (MCCD) were included. Eligible patients had CLL, were previously treated, were aged 18 years or older, had ECOG performance status 0–1, and required further treatment as per the international workshop on CLL 2008 criteria. There was heterogeneity in other eligibility criteria. We evaluated 28 candidate factors known to affect the overall survival of these patients and applied univariate and multivariate analyses to derive the risk score in a training dataset (n=727) of patients treated with ibrutinib or chemoimmunotherapy. We validated the score in an internal-validation dataset (n=242) of patients treated with ibrutinib or chemoimmunotherapy and three external-validation datasets (idelalisib or chemoimmunotherapy dataset, n=897; venetoclax or chemoimmunotherapy dataset, n=389; and the MCCD [including patients treated with heterogeneous therapies], n=220), applying C-statistics as a measure of discrimination. Findings: The derived model consisted of four factors (one point each; serum β2-microglobulin ≥5 mg/dL, lactate dehydrogenase >upper limit of normal, haemoglobin <110 g/L for women or <120 g/L for men, and time from initiation of last therapy <24 months), separating patients into low (score 0–1), intermediate (score 2–3), and high risk (score 4) groups. The risk score was prognostic for overall survival in the training dataset (CS=0·74, 95% CI 0·60–0·85, log-rank p<0·0001), and in the internal-validation (CS=0·79, 0·56–0·97, log-rank p=0·0003), and all three external-validation cohorts (idelalisib or chemoimmunotherapy: CS=0·71, 0·59–0·81, log-rank p<0·0001; venetoclax or chemoimmunotherapy: CS =0·76, 0·66–0·85, log-rank p=0·014; MCCD cohort: CS=0·61, 0·56–0·66), log-rank p<0·0001). The risk score is available on Calculate by QxMD. Interpretation: We present the first validated risk score to predict overall survival in patients with relapsed or refractory CLL treated with targeted therapy. The model is applicable to patients treated with all currently approved targeted therapies (ibrutinib, idelalisib, and venetoclax) and chemoimmunotherapy. This tool allows the identification of a well defined cohort of previously treated patients with CLL who are at high risk of death, and could be used in future prospective trials to test therapeutic options for these patients with an unmet clinical need. Funding: Lymphoma Research Foundation, Lymphoma Research Fund (Andrew D Zelenetz), and National Institutes of Health/National Cancer Institute.
AB - Background: Clinically validated prognostic models for overall survival do not exist for patients with relapsed or refractory chronic lymphocytic leukaemia (CLL) who are on targeted therapies. We aimed to create a prognostic model to identify high-risk individuals who do not achieve a good outcome with available targeted therapies. Methods: In this retrospective, pooled cohort study, 2475 patients with CLL treated between June 22, 2012, and Sept 23, 2015, in six randomised trials of ibrutinib, idelalisib, and venetoclax, or at the Mayo Clinic CLL Database (MCCD) were included. Eligible patients had CLL, were previously treated, were aged 18 years or older, had ECOG performance status 0–1, and required further treatment as per the international workshop on CLL 2008 criteria. There was heterogeneity in other eligibility criteria. We evaluated 28 candidate factors known to affect the overall survival of these patients and applied univariate and multivariate analyses to derive the risk score in a training dataset (n=727) of patients treated with ibrutinib or chemoimmunotherapy. We validated the score in an internal-validation dataset (n=242) of patients treated with ibrutinib or chemoimmunotherapy and three external-validation datasets (idelalisib or chemoimmunotherapy dataset, n=897; venetoclax or chemoimmunotherapy dataset, n=389; and the MCCD [including patients treated with heterogeneous therapies], n=220), applying C-statistics as a measure of discrimination. Findings: The derived model consisted of four factors (one point each; serum β2-microglobulin ≥5 mg/dL, lactate dehydrogenase >upper limit of normal, haemoglobin <110 g/L for women or <120 g/L for men, and time from initiation of last therapy <24 months), separating patients into low (score 0–1), intermediate (score 2–3), and high risk (score 4) groups. The risk score was prognostic for overall survival in the training dataset (CS=0·74, 95% CI 0·60–0·85, log-rank p<0·0001), and in the internal-validation (CS=0·79, 0·56–0·97, log-rank p=0·0003), and all three external-validation cohorts (idelalisib or chemoimmunotherapy: CS=0·71, 0·59–0·81, log-rank p<0·0001; venetoclax or chemoimmunotherapy: CS =0·76, 0·66–0·85, log-rank p=0·014; MCCD cohort: CS=0·61, 0·56–0·66), log-rank p<0·0001). The risk score is available on Calculate by QxMD. Interpretation: We present the first validated risk score to predict overall survival in patients with relapsed or refractory CLL treated with targeted therapy. The model is applicable to patients treated with all currently approved targeted therapies (ibrutinib, idelalisib, and venetoclax) and chemoimmunotherapy. This tool allows the identification of a well defined cohort of previously treated patients with CLL who are at high risk of death, and could be used in future prospective trials to test therapeutic options for these patients with an unmet clinical need. Funding: Lymphoma Research Foundation, Lymphoma Research Fund (Andrew D Zelenetz), and National Institutes of Health/National Cancer Institute.
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U2 - 10.1016/S2352-3026(19)30085-7
DO - 10.1016/S2352-3026(19)30085-7
M3 - Article
C2 - 31109827
AN - SCOPUS:85067669822
VL - 6
SP - e366-e374
JO - The Lancet Haematology
JF - The Lancet Haematology
SN - 2352-3026
IS - 7
ER -