The Chronic Lymphocytic Leukemia Comorbidity Index (CLL-CI) Predicts Survival and Tolerance of Ibrutinib Therapy in Patients with CLL: A Multicenter Retrospective Cohort Study
Introduction: Medical comorbidities influence survival in CLL. We previously reported on a simplified CLL-specific comorbidity scale, the CLL-CI (Gordon et al. 2019), which required assessment of only three organ systems and was predictive of outcomes in a heterogeneous retrospective patient cohort....
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| Veröffentlicht in: | Blood 2020-11, Vol.136 (Supplement 1), p.1-3 |
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| creator | Gordon, Max J. Kaempf, Andy Sitlinger, Andrea Salous, Tareq Alqahtani, Hamood Churnetski, Michael C. Wisniewski, Paul Rivera, Xavier Issac Patel, Krish Persky, Daniel O. Cohen, Jonathon B. Choi, Michael Y. Hill, Brian T. Shadman, Mazyar Stephens, Deborah M. Brander, Danielle M. Park, Byung Danilov, Alexey |
| description | Introduction: Medical comorbidities influence survival in CLL. We previously reported on a simplified CLL-specific comorbidity scale, the CLL-CI (Gordon et al. 2019), which required assessment of only three organ systems and was predictive of outcomes in a heterogeneous retrospective patient cohort. Herein we analyzed CLL-CI among patients treated with ibrutinib.
Methods: This retrospective study included 339 CLL patients treated with ibrutinib at 9 academic centers between 2014-2019. Vascular, endocrine and upper-gastrointestinal organ systems were assessed at the time of ibrutinib initiation. Each was scored from 0 to 3, in order of increasing severity of dysfunction to generate the CLL-CI score (range, 0-9; Figure A). As established previously, CLL-CI≥2 was deemed high-risk. Event free survival (EFS) was measured from start of ibrutinib to development of new CLL-related symptoms, disease progression, start of a new therapy or death. Overall survival (OS) was measured from treatment initiation to death. Patients with no EFS or OS events were censored at last follow up. The Kaplan-Meier method and log-rank test were used to estimate and compare survival. Multivariable Cox regression was utilized to model EFS and OS. Differences between CLL-CI groups were evaluated with Wilcoxon rank sum and Fisher’s exact tests.
Results: Median age was 68 years (range, 30-91), 240 (71%) were treated in the relapsed/refractory setting (range of prior therapies, 0-10). Advanced Rai stage (3-4) was present in 206 (61%) and TP53 aberrancy was present in 93 (27%) patients at the start of ibrutinib therapy. Median follow up was 23 months (range, 1-71).
CLL-CI score was high (≥2) in 202/339 patients (60%). Patient characteristics were well balanced between subgroups (CLL-CI |
| doi_str_mv | 10.1182/blood-2020-136808 |
| format | Article |
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Methods: This retrospective study included 339 CLL patients treated with ibrutinib at 9 academic centers between 2014-2019. Vascular, endocrine and upper-gastrointestinal organ systems were assessed at the time of ibrutinib initiation. Each was scored from 0 to 3, in order of increasing severity of dysfunction to generate the CLL-CI score (range, 0-9; Figure A). As established previously, CLL-CI≥2 was deemed high-risk. Event free survival (EFS) was measured from start of ibrutinib to development of new CLL-related symptoms, disease progression, start of a new therapy or death. Overall survival (OS) was measured from treatment initiation to death. Patients with no EFS or OS events were censored at last follow up. The Kaplan-Meier method and log-rank test were used to estimate and compare survival. Multivariable Cox regression was utilized to model EFS and OS. Differences between CLL-CI groups were evaluated with Wilcoxon rank sum and Fisher’s exact tests.
Results: Median age was 68 years (range, 30-91), 240 (71%) were treated in the relapsed/refractory setting (range of prior therapies, 0-10). Advanced Rai stage (3-4) was present in 206 (61%) and TP53 aberrancy was present in 93 (27%) patients at the start of ibrutinib therapy. Median follow up was 23 months (range, 1-71).
CLL-CI score was high (≥2) in 202/339 patients (60%). Patient characteristics were well balanced between subgroups (CLL-CI <2 vs ≥2). The median number of prior therapies was 1 in both groups. The distribution of Rai stage, TP53 aberrancy and IGHV mutational status (available in 48% of patients), were similar.
In multivariate models adjusted for age, del(17p) and relapsed disease, high CLL-CI was associated with shortened EFS (HR=1.65; p=0.014, Figure) and OS (HR=1.73; p=0.1). CIRS score≥7 also correlated with EFS (HR=1.91; p=0.002) and OS (HR=2.78; p=0.006). Ibrutinib discontinuation rates due to adverse events were more frequent in patients with CLL-CI ≥2 (25% vs 14%; p=0.014). However, dose reduction rates were similar (24% vs 20%; p=0.51).
Fifty-two deaths occurred: 40 in the high CLL-CI subgroup and 12 in the low CLL-CI subgroup. Cause of death was known in 31 patients. Death due to disease progression was more frequent in the high CLL-CI subgroup (28% vs 8%; p<0.001). Infection was the second most common cause of death and occurred at a similar rate in both groups (13% vs 16%; p=0.66). Two deaths occurred due to cardiac causes, both in the high CLL-CI group.
Since some of the key ibrutinib toxicities (atrial fibrillation, hypertension) may not have been accounted for in the CLL-CI we further elucidated their possible impact. Cardiac disease was significantly more prevalent among patients with high CLL-CI (37% vs 16%, p<0.001; severe - 13% vs 5%; p=0.013) as was hypertension (63% vs 35%; p<0.001; severe - 27% vs 13%; p=0.004). When computing pairwise correlation coefficients, we found that vascular and endocrine comorbidities significantly correlated with both cardiac disease and hypertension (Spearman ρ = 0.15 to 0.27). However, re-computing CLL-CI score upon inclusion of those categories did not influence the EFS concordance probability (CLL-CI, 0.669 vs CLL-CI plus cardiac and hypertension, 0.664).
Conclusions: Here we present the largest cohort of CLL patients treated with ibrutinib in whom comorbidities have been systematically assessed. We find that the CLL-CI (which assesses endocrine, vascular and upper gastrointestinal conditions) correlates with survival and tolerance of therapy in this population. Unexpectedly, we found that hypertension and cardiac comorbidities did not improve CLL-CI's discriminatory power. This result combined with the simplicity of scoring the CLL-CI makes it an attractive tool for clinical practice. CLL-CI needs to be explored prospectively in patients treated with ibrutinib and other targeted therapies.
[Display omitted]
Patel:Genentech: Consultancy, Speakers Bureau; BeiGene: Consultancy; Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Speakers Bureau; Adaptive Biotechnologies: Consultancy; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Speakers Bureau; Kite: Consultancy. Cohen:Janssen, Adicet, Astra Zeneca, Genentech, Aptitude Health, Cellectar, Kite/Gilead, Loxo: Consultancy; Genentech, BMS, Novartis, LAM, BioInvent, LRF, ASH, Astra Zeneca, Seattle Genetics: Research Funding. Choi:Pharmacyclics/Abbvie: Research Funding; Genentech: Consultancy. Hill:BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; Takeda: Research Funding; Beigene: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding. Shadman:Mustang Bio, Celgene, Pharmacyclics, Gilead, Genentech, Abbvie, TG therapeutics, Beigene, Astra Zeneca, Sunesis, Beigene: Research Funding; Abbvie, Genentech, Astra Zeneca, Sound Biologics , Pharmacyclics, Verastem, ADC therapeutics, Beigene, Cellectar, BMS, Morphosys and Atara Biotherapeutics: Consultancy. Stephens:Innate: Consultancy; Gilead: Research Funding; Verastem: Research Funding; Janssen: Consultancy; Acerta: Research Funding; Pharmacyclics: Consultancy; MingSight: Research Funding; Beigene: Consultancy; Arqule: Research Funding; Juno: Research Funding; Karyopharm: Consultancy, Research Funding. Brander:Novartis: Consultancy, Other; NCCN: Other; Tolero: Research Funding; AstraZeneca: Consultancy, Honoraria, Other, Research Funding; Ascentage: Other, Research Funding; ArQule: Consultancy, Other, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Tolero: Research Funding; Teva: Consultancy, Honoraria; Novartis: Consultancy, Other; NCCN: Other; Verastem: Consultancy, Honoraria, Other, Research Funding; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Pfizer: Consultancy, Other; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Other, Research Funding; MEI Pharma: Other, Research Funding; Juno/Celgene/BMS: Other, Research Funding; Genentech: Consultancy, Honoraria, Other, Research Funding; DTRM: Other, Research Funding; BeiGene: Other, Research Funding; Teva: Consultancy, Honoraria. Danilov:BeiGene: Consultancy; Pharmacyclics: Consultancy; Abbvie: Consultancy; Bristol-Myers Squibb: Research Funding; Rigel Pharmaceuticals: Consultancy; Astra Zeneca: Consultancy, Research Funding; Aptose Biosciences: Research Funding; Verastem Oncology: Consultancy, Research Funding; Takeda Oncology: Research Funding; Gilead Sciences: Research Funding; Bayer Oncology: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; TG Therapeutics: Consultancy; Nurix: Consultancy; Celgene: Consultancy; Karyopharm: Consultancy.</description><identifier>ISSN: 0006-4971</identifier><identifier>EISSN: 1528-0020</identifier><identifier>DOI: 10.1182/blood-2020-136808</identifier><language>eng</language><publisher>Elsevier Inc</publisher><ispartof>Blood, 2020-11, Vol.136 (Supplement 1), p.1-3</ispartof><rights>2020 American Society of Hematology</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784,27924,27925</link.rule.ids></links><search><creatorcontrib>Gordon, Max J.</creatorcontrib><creatorcontrib>Kaempf, Andy</creatorcontrib><creatorcontrib>Sitlinger, Andrea</creatorcontrib><creatorcontrib>Salous, Tareq</creatorcontrib><creatorcontrib>Alqahtani, Hamood</creatorcontrib><creatorcontrib>Churnetski, Michael C.</creatorcontrib><creatorcontrib>Wisniewski, Paul</creatorcontrib><creatorcontrib>Rivera, Xavier Issac</creatorcontrib><creatorcontrib>Patel, Krish</creatorcontrib><creatorcontrib>Persky, Daniel O.</creatorcontrib><creatorcontrib>Cohen, Jonathon B.</creatorcontrib><creatorcontrib>Choi, Michael Y.</creatorcontrib><creatorcontrib>Hill, Brian T.</creatorcontrib><creatorcontrib>Shadman, Mazyar</creatorcontrib><creatorcontrib>Stephens, Deborah M.</creatorcontrib><creatorcontrib>Brander, Danielle M.</creatorcontrib><creatorcontrib>Park, Byung</creatorcontrib><creatorcontrib>Danilov, Alexey</creatorcontrib><title>The Chronic Lymphocytic Leukemia Comorbidity Index (CLL-CI) Predicts Survival and Tolerance of Ibrutinib Therapy in Patients with CLL: A Multicenter Retrospective Cohort Study</title><title>Blood</title><description>Introduction: Medical comorbidities influence survival in CLL. We previously reported on a simplified CLL-specific comorbidity scale, the CLL-CI (Gordon et al. 2019), which required assessment of only three organ systems and was predictive of outcomes in a heterogeneous retrospective patient cohort. Herein we analyzed CLL-CI among patients treated with ibrutinib.
Methods: This retrospective study included 339 CLL patients treated with ibrutinib at 9 academic centers between 2014-2019. Vascular, endocrine and upper-gastrointestinal organ systems were assessed at the time of ibrutinib initiation. Each was scored from 0 to 3, in order of increasing severity of dysfunction to generate the CLL-CI score (range, 0-9; Figure A). As established previously, CLL-CI≥2 was deemed high-risk. Event free survival (EFS) was measured from start of ibrutinib to development of new CLL-related symptoms, disease progression, start of a new therapy or death. Overall survival (OS) was measured from treatment initiation to death. Patients with no EFS or OS events were censored at last follow up. The Kaplan-Meier method and log-rank test were used to estimate and compare survival. Multivariable Cox regression was utilized to model EFS and OS. Differences between CLL-CI groups were evaluated with Wilcoxon rank sum and Fisher’s exact tests.
Results: Median age was 68 years (range, 30-91), 240 (71%) were treated in the relapsed/refractory setting (range of prior therapies, 0-10). Advanced Rai stage (3-4) was present in 206 (61%) and TP53 aberrancy was present in 93 (27%) patients at the start of ibrutinib therapy. Median follow up was 23 months (range, 1-71).
CLL-CI score was high (≥2) in 202/339 patients (60%). Patient characteristics were well balanced between subgroups (CLL-CI <2 vs ≥2). The median number of prior therapies was 1 in both groups. The distribution of Rai stage, TP53 aberrancy and IGHV mutational status (available in 48% of patients), were similar.
In multivariate models adjusted for age, del(17p) and relapsed disease, high CLL-CI was associated with shortened EFS (HR=1.65; p=0.014, Figure) and OS (HR=1.73; p=0.1). CIRS score≥7 also correlated with EFS (HR=1.91; p=0.002) and OS (HR=2.78; p=0.006). Ibrutinib discontinuation rates due to adverse events were more frequent in patients with CLL-CI ≥2 (25% vs 14%; p=0.014). However, dose reduction rates were similar (24% vs 20%; p=0.51).
Fifty-two deaths occurred: 40 in the high CLL-CI subgroup and 12 in the low CLL-CI subgroup. Cause of death was known in 31 patients. Death due to disease progression was more frequent in the high CLL-CI subgroup (28% vs 8%; p<0.001). Infection was the second most common cause of death and occurred at a similar rate in both groups (13% vs 16%; p=0.66). Two deaths occurred due to cardiac causes, both in the high CLL-CI group.
Since some of the key ibrutinib toxicities (atrial fibrillation, hypertension) may not have been accounted for in the CLL-CI we further elucidated their possible impact. Cardiac disease was significantly more prevalent among patients with high CLL-CI (37% vs 16%, p<0.001; severe - 13% vs 5%; p=0.013) as was hypertension (63% vs 35%; p<0.001; severe - 27% vs 13%; p=0.004). When computing pairwise correlation coefficients, we found that vascular and endocrine comorbidities significantly correlated with both cardiac disease and hypertension (Spearman ρ = 0.15 to 0.27). However, re-computing CLL-CI score upon inclusion of those categories did not influence the EFS concordance probability (CLL-CI, 0.669 vs CLL-CI plus cardiac and hypertension, 0.664).
Conclusions: Here we present the largest cohort of CLL patients treated with ibrutinib in whom comorbidities have been systematically assessed. We find that the CLL-CI (which assesses endocrine, vascular and upper gastrointestinal conditions) correlates with survival and tolerance of therapy in this population. Unexpectedly, we found that hypertension and cardiac comorbidities did not improve CLL-CI's discriminatory power. This result combined with the simplicity of scoring the CLL-CI makes it an attractive tool for clinical practice. CLL-CI needs to be explored prospectively in patients treated with ibrutinib and other targeted therapies.
[Display omitted]
Patel:Genentech: Consultancy, Speakers Bureau; BeiGene: Consultancy; Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Speakers Bureau; Adaptive Biotechnologies: Consultancy; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Speakers Bureau; Kite: Consultancy. Cohen:Janssen, Adicet, Astra Zeneca, Genentech, Aptitude Health, Cellectar, Kite/Gilead, Loxo: Consultancy; Genentech, BMS, Novartis, LAM, BioInvent, LRF, ASH, Astra Zeneca, Seattle Genetics: Research Funding. Choi:Pharmacyclics/Abbvie: Research Funding; Genentech: Consultancy. Hill:BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; Takeda: Research Funding; Beigene: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding. Shadman:Mustang Bio, Celgene, Pharmacyclics, Gilead, Genentech, Abbvie, TG therapeutics, Beigene, Astra Zeneca, Sunesis, Beigene: Research Funding; Abbvie, Genentech, Astra Zeneca, Sound Biologics , Pharmacyclics, Verastem, ADC therapeutics, Beigene, Cellectar, BMS, Morphosys and Atara Biotherapeutics: Consultancy. Stephens:Innate: Consultancy; Gilead: Research Funding; Verastem: Research Funding; Janssen: Consultancy; Acerta: Research Funding; Pharmacyclics: Consultancy; MingSight: Research Funding; Beigene: Consultancy; Arqule: Research Funding; Juno: Research Funding; Karyopharm: Consultancy, Research Funding. Brander:Novartis: Consultancy, Other; NCCN: Other; Tolero: Research Funding; AstraZeneca: Consultancy, Honoraria, Other, Research Funding; Ascentage: Other, Research Funding; ArQule: Consultancy, Other, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Tolero: Research Funding; Teva: Consultancy, Honoraria; Novartis: Consultancy, Other; NCCN: Other; Verastem: Consultancy, Honoraria, Other, Research Funding; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Pfizer: Consultancy, Other; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Other, Research Funding; MEI Pharma: Other, Research Funding; Juno/Celgene/BMS: Other, Research Funding; Genentech: Consultancy, Honoraria, Other, Research Funding; DTRM: Other, Research Funding; BeiGene: Other, Research Funding; Teva: Consultancy, Honoraria. Danilov:BeiGene: Consultancy; Pharmacyclics: Consultancy; Abbvie: Consultancy; Bristol-Myers Squibb: Research Funding; Rigel Pharmaceuticals: Consultancy; Astra Zeneca: Consultancy, Research Funding; Aptose Biosciences: Research Funding; Verastem Oncology: Consultancy, Research Funding; Takeda Oncology: Research Funding; Gilead Sciences: Research Funding; Bayer Oncology: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; TG Therapeutics: Consultancy; Nurix: Consultancy; Celgene: Consultancy; Karyopharm: Consultancy.</description><issn>0006-4971</issn><issn>1528-0020</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><recordid>eNp9kM1O3DAUha0KpE6BB-juLttFiu2QxAMrFFEYKagjZlhH_rlR3GbikeOE5ql4RTwMa1b3Rzr3nvMR8p3RX4wJfqk650zCKacJS3NBxReyYBkXCY2rE7KglObJ1bJgX8m3YfhLKbtKebYgr9sWoWy9662Gat7tW6fncOhx_Ic7K6F0O-eVNTbMsOoN_ocfZVUl5eonrD0aq8MAm9FPdpIdyN7A1nXoZa8RXAMr5cdge6sgPvJyP4PtYS2DxT7qXmxoIV67hlt4HLv4N67RwxMG74Y96mCnaM-1zgfYhNHM5-S0kd2AFx_1jDz_vtuWD0n1535V3laJZmkhEpS6yDKNyLN8mWojuFAaed5gsaRMCUzjTFEuG8MLpZDSNMtzJSRKo0wm0zPCjnd1NDJ4bOq9tzvp55rR-kC8fideH4jXR-JRc3PUYDQ2WfT1oGNOHSH5GKU2zn6ifgMP7Y0V</recordid><startdate>20201105</startdate><enddate>20201105</enddate><creator>Gordon, Max J.</creator><creator>Kaempf, Andy</creator><creator>Sitlinger, Andrea</creator><creator>Salous, Tareq</creator><creator>Alqahtani, Hamood</creator><creator>Churnetski, Michael C.</creator><creator>Wisniewski, Paul</creator><creator>Rivera, Xavier Issac</creator><creator>Patel, Krish</creator><creator>Persky, Daniel O.</creator><creator>Cohen, Jonathon B.</creator><creator>Choi, Michael Y.</creator><creator>Hill, Brian T.</creator><creator>Shadman, Mazyar</creator><creator>Stephens, Deborah M.</creator><creator>Brander, Danielle M.</creator><creator>Park, Byung</creator><creator>Danilov, Alexey</creator><general>Elsevier Inc</general><scope>AAYXX</scope><scope>CITATION</scope></search><sort><creationdate>20201105</creationdate><title>The Chronic Lymphocytic Leukemia Comorbidity Index (CLL-CI) Predicts Survival and Tolerance of Ibrutinib Therapy in Patients with CLL: A Multicenter Retrospective Cohort Study</title><author>Gordon, Max J. ; Kaempf, Andy ; Sitlinger, Andrea ; Salous, Tareq ; Alqahtani, Hamood ; Churnetski, Michael C. ; Wisniewski, Paul ; Rivera, Xavier Issac ; Patel, Krish ; Persky, Daniel O. ; Cohen, Jonathon B. ; Choi, Michael Y. ; Hill, Brian T. ; Shadman, Mazyar ; Stephens, Deborah M. ; Brander, Danielle M. ; Park, Byung ; Danilov, Alexey</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c1378-eac755cee25693cd828bce26fe7901b8e38bc0ea9fd27bbe003566b8aeadbd5a3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Gordon, Max J.</creatorcontrib><creatorcontrib>Kaempf, Andy</creatorcontrib><creatorcontrib>Sitlinger, Andrea</creatorcontrib><creatorcontrib>Salous, Tareq</creatorcontrib><creatorcontrib>Alqahtani, Hamood</creatorcontrib><creatorcontrib>Churnetski, Michael C.</creatorcontrib><creatorcontrib>Wisniewski, Paul</creatorcontrib><creatorcontrib>Rivera, Xavier Issac</creatorcontrib><creatorcontrib>Patel, Krish</creatorcontrib><creatorcontrib>Persky, Daniel O.</creatorcontrib><creatorcontrib>Cohen, Jonathon B.</creatorcontrib><creatorcontrib>Choi, Michael Y.</creatorcontrib><creatorcontrib>Hill, Brian T.</creatorcontrib><creatorcontrib>Shadman, Mazyar</creatorcontrib><creatorcontrib>Stephens, Deborah M.</creatorcontrib><creatorcontrib>Brander, Danielle M.</creatorcontrib><creatorcontrib>Park, Byung</creatorcontrib><creatorcontrib>Danilov, Alexey</creatorcontrib><collection>CrossRef</collection><jtitle>Blood</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Gordon, Max J.</au><au>Kaempf, Andy</au><au>Sitlinger, Andrea</au><au>Salous, Tareq</au><au>Alqahtani, Hamood</au><au>Churnetski, Michael C.</au><au>Wisniewski, Paul</au><au>Rivera, Xavier Issac</au><au>Patel, Krish</au><au>Persky, Daniel O.</au><au>Cohen, Jonathon B.</au><au>Choi, Michael Y.</au><au>Hill, Brian T.</au><au>Shadman, Mazyar</au><au>Stephens, Deborah M.</au><au>Brander, Danielle M.</au><au>Park, Byung</au><au>Danilov, Alexey</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The Chronic Lymphocytic Leukemia Comorbidity Index (CLL-CI) Predicts Survival and Tolerance of Ibrutinib Therapy in Patients with CLL: A Multicenter Retrospective Cohort Study</atitle><jtitle>Blood</jtitle><date>2020-11-05</date><risdate>2020</risdate><volume>136</volume><issue>Supplement 1</issue><spage>1</spage><epage>3</epage><pages>1-3</pages><issn>0006-4971</issn><eissn>1528-0020</eissn><abstract>Introduction: Medical comorbidities influence survival in CLL. We previously reported on a simplified CLL-specific comorbidity scale, the CLL-CI (Gordon et al. 2019), which required assessment of only three organ systems and was predictive of outcomes in a heterogeneous retrospective patient cohort. Herein we analyzed CLL-CI among patients treated with ibrutinib.
Methods: This retrospective study included 339 CLL patients treated with ibrutinib at 9 academic centers between 2014-2019. Vascular, endocrine and upper-gastrointestinal organ systems were assessed at the time of ibrutinib initiation. Each was scored from 0 to 3, in order of increasing severity of dysfunction to generate the CLL-CI score (range, 0-9; Figure A). As established previously, CLL-CI≥2 was deemed high-risk. Event free survival (EFS) was measured from start of ibrutinib to development of new CLL-related symptoms, disease progression, start of a new therapy or death. Overall survival (OS) was measured from treatment initiation to death. Patients with no EFS or OS events were censored at last follow up. The Kaplan-Meier method and log-rank test were used to estimate and compare survival. Multivariable Cox regression was utilized to model EFS and OS. Differences between CLL-CI groups were evaluated with Wilcoxon rank sum and Fisher’s exact tests.
Results: Median age was 68 years (range, 30-91), 240 (71%) were treated in the relapsed/refractory setting (range of prior therapies, 0-10). Advanced Rai stage (3-4) was present in 206 (61%) and TP53 aberrancy was present in 93 (27%) patients at the start of ibrutinib therapy. Median follow up was 23 months (range, 1-71).
CLL-CI score was high (≥2) in 202/339 patients (60%). Patient characteristics were well balanced between subgroups (CLL-CI <2 vs ≥2). The median number of prior therapies was 1 in both groups. The distribution of Rai stage, TP53 aberrancy and IGHV mutational status (available in 48% of patients), were similar.
In multivariate models adjusted for age, del(17p) and relapsed disease, high CLL-CI was associated with shortened EFS (HR=1.65; p=0.014, Figure) and OS (HR=1.73; p=0.1). CIRS score≥7 also correlated with EFS (HR=1.91; p=0.002) and OS (HR=2.78; p=0.006). Ibrutinib discontinuation rates due to adverse events were more frequent in patients with CLL-CI ≥2 (25% vs 14%; p=0.014). However, dose reduction rates were similar (24% vs 20%; p=0.51).
Fifty-two deaths occurred: 40 in the high CLL-CI subgroup and 12 in the low CLL-CI subgroup. Cause of death was known in 31 patients. Death due to disease progression was more frequent in the high CLL-CI subgroup (28% vs 8%; p<0.001). Infection was the second most common cause of death and occurred at a similar rate in both groups (13% vs 16%; p=0.66). Two deaths occurred due to cardiac causes, both in the high CLL-CI group.
Since some of the key ibrutinib toxicities (atrial fibrillation, hypertension) may not have been accounted for in the CLL-CI we further elucidated their possible impact. Cardiac disease was significantly more prevalent among patients with high CLL-CI (37% vs 16%, p<0.001; severe - 13% vs 5%; p=0.013) as was hypertension (63% vs 35%; p<0.001; severe - 27% vs 13%; p=0.004). When computing pairwise correlation coefficients, we found that vascular and endocrine comorbidities significantly correlated with both cardiac disease and hypertension (Spearman ρ = 0.15 to 0.27). However, re-computing CLL-CI score upon inclusion of those categories did not influence the EFS concordance probability (CLL-CI, 0.669 vs CLL-CI plus cardiac and hypertension, 0.664).
Conclusions: Here we present the largest cohort of CLL patients treated with ibrutinib in whom comorbidities have been systematically assessed. We find that the CLL-CI (which assesses endocrine, vascular and upper gastrointestinal conditions) correlates with survival and tolerance of therapy in this population. Unexpectedly, we found that hypertension and cardiac comorbidities did not improve CLL-CI's discriminatory power. This result combined with the simplicity of scoring the CLL-CI makes it an attractive tool for clinical practice. CLL-CI needs to be explored prospectively in patients treated with ibrutinib and other targeted therapies.
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Patel:Genentech: Consultancy, Speakers Bureau; BeiGene: Consultancy; Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Speakers Bureau; Adaptive Biotechnologies: Consultancy; AstraZeneca: Consultancy, Research Funding, Speakers Bureau; Pharmacyclics: Consultancy, Speakers Bureau; Kite: Consultancy. Cohen:Janssen, Adicet, Astra Zeneca, Genentech, Aptitude Health, Cellectar, Kite/Gilead, Loxo: Consultancy; Genentech, BMS, Novartis, LAM, BioInvent, LRF, ASH, Astra Zeneca, Seattle Genetics: Research Funding. Choi:Pharmacyclics/Abbvie: Research Funding; Genentech: Consultancy. Hill:BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria, Research Funding; Takeda: Research Funding; Beigene: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding. Shadman:Mustang Bio, Celgene, Pharmacyclics, Gilead, Genentech, Abbvie, TG therapeutics, Beigene, Astra Zeneca, Sunesis, Beigene: Research Funding; Abbvie, Genentech, Astra Zeneca, Sound Biologics , Pharmacyclics, Verastem, ADC therapeutics, Beigene, Cellectar, BMS, Morphosys and Atara Biotherapeutics: Consultancy. Stephens:Innate: Consultancy; Gilead: Research Funding; Verastem: Research Funding; Janssen: Consultancy; Acerta: Research Funding; Pharmacyclics: Consultancy; MingSight: Research Funding; Beigene: Consultancy; Arqule: Research Funding; Juno: Research Funding; Karyopharm: Consultancy, Research Funding. Brander:Novartis: Consultancy, Other; NCCN: Other; Tolero: Research Funding; AstraZeneca: Consultancy, Honoraria, Other, Research Funding; Ascentage: Other, Research Funding; ArQule: Consultancy, Other, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Tolero: Research Funding; Teva: Consultancy, Honoraria; Novartis: Consultancy, Other; NCCN: Other; Verastem: Consultancy, Honoraria, Other, Research Funding; TG Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Pfizer: Consultancy, Other; Pharmacyclics LLC, an AbbVie Company: Consultancy, Honoraria, Other, Research Funding; MEI Pharma: Other, Research Funding; Juno/Celgene/BMS: Other, Research Funding; Genentech: Consultancy, Honoraria, Other, Research Funding; DTRM: Other, Research Funding; BeiGene: Other, Research Funding; Teva: Consultancy, Honoraria. Danilov:BeiGene: Consultancy; Pharmacyclics: Consultancy; Abbvie: Consultancy; Bristol-Myers Squibb: Research Funding; Rigel Pharmaceuticals: Consultancy; Astra Zeneca: Consultancy, Research Funding; Aptose Biosciences: Research Funding; Verastem Oncology: Consultancy, Research Funding; Takeda Oncology: Research Funding; Gilead Sciences: Research Funding; Bayer Oncology: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; TG Therapeutics: Consultancy; Nurix: Consultancy; Celgene: Consultancy; Karyopharm: Consultancy.</abstract><pub>Elsevier Inc</pub><doi>10.1182/blood-2020-136808</doi><tpages>3</tpages><oa>free_for_read</oa></addata></record> |
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| title | The Chronic Lymphocytic Leukemia Comorbidity Index (CLL-CI) Predicts Survival and Tolerance of Ibrutinib Therapy in Patients with CLL: A Multicenter Retrospective Cohort Study |
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