{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,31]],"date-time":"2026-10-31T11:04:57Z","timestamp":1793444697498,"version":"4.5.0"},"reference-count":33,"publisher":"American Medical Association (AMA)","issue":"9","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Oncol"],"published-print":{"date-parts":[[2024,9,1]]},"abstract":"<jats:sec id=\"ab-coi240030-4\"><jats:title>Importance<\/jats:title><jats:p>Measurable residual disease (MRD) refers to the presence of disease at low levels not detected by conventional pathologic analysis. The association of MRD status as a surrogate end point of clinical outcome in chronic lymphocytic leukemia (CLL) has not been established in the era of targeted agents. Assessing the association of MRD with progression-free survival (PFS) may improve its role as a surrogate marker and allow its use to accelerate drug development.<\/jats:p><\/jats:sec><jats:sec id=\"ab-coi240030-5\"><jats:title>Objective<\/jats:title><jats:p>To assess the association between MRD and PFS in CLL using data from prospective clinical trials that studied targeted agents or obinutuzumab-based treatment.<\/jats:p><\/jats:sec><jats:sec id=\"ab-coi240030-6\"><jats:title>Data Sources<\/jats:title><jats:p>Clinical studies on CLL were identified via searches of PubMed, Embase, Scopus, and Web of Science from inception through July 31, 2023.<\/jats:p><\/jats:sec><jats:sec id=\"ab-coi240030-7\"><jats:title>Study Selection<\/jats:title><jats:p>Prospective, single-arm, and randomized clinical trials that assessed targeted agents or obinutuzumab-based treatment and reported PFS by MRD status were included. Studies with insufficient description of MRD information were excluded.<\/jats:p><\/jats:sec><jats:sec id=\"ab-coi240030-8\"><jats:title>Data Extraction and Synthesis<\/jats:title><jats:p>Study sample size, median patient age, median follow-up time, line of treatment, MRD detection method and time points, and survival outcomes were extracted.<\/jats:p><\/jats:sec><jats:sec id=\"ab-coi240030-9\"><jats:title>Main Outcomes and Measures<\/jats:title><jats:p>Analyses of survival probabilities and hazard ratios (HRs) were conducted for PFS according to MRD status. Meta-analyses were performed using a random-effects model.<\/jats:p><\/jats:sec><jats:sec id=\"ab-coi240030-10\"><jats:title>Results<\/jats:title><jats:p>A total of 11 prospective clinical trials (9 randomized and 2 nonrandomized) including 2765 patients were analyzed. Achieving undetectable MRD (uMRD) at 0.01% was associated with an HR of 0.28 (95% CI, 0.20-0.39; <jats:italic>P<\/jats:italic>\u2009&amp;amp;lt;\u2009.001) for PFS. Median PFS was not reached in both groups (uMRD vs MRD), but the estimated 24-month PFS was better in the uMRD group (91.9% [95% CI, 88.8%-95.2%] vs 75.3% [95% CI, 64.7%-87.6%]; <jats:italic>P<\/jats:italic>\u2009&amp;amp;lt;\u2009.001). The association of uMRD with PFS was observed in subgroup analyses in the first-line treatment setting (HR, 0.24; 95% CI, 0.18-0.33), relapsed or refractory disease setting (HR, 0.34; 95% CI, 0.16-0.71), and trials using time-limited therapy (HR, 0.28; 95% CI, 0.19-0.40).<\/jats:p><\/jats:sec><jats:sec id=\"ab-coi240030-11\"><jats:title>Conclusions and Relevance<\/jats:title><jats:p>The findings of this systematic review and meta-analysis suggest that assessing MRD status as an end point in clinical trials and as a surrogate of PFS may improve trial efficiency and potentially allow for accelerated drug registration.<\/jats:p><\/jats:sec>","DOI":"10.1001\/jamaoncol.2024.2122","type":"journal-article","created":{"date-parts":[[2024,7,11]],"date-time":"2024-07-11T15:40:21Z","timestamp":1720712421000},"page":"1221","source":"Crossref","is-referenced-by-count":9,"title":["Measurable Residual Disease and Clinical Outcomes in Chronic Lymphocytic Leukemia"],"prefix":"10.1001","volume":"10","author":[{"given":"Fausto Alfredo","family":"Rios-Olais","sequence":"first","affiliation":[{"name":"Hematology and Oncology Department, Instituto Nacional de Ciencias M\u00e9dicas y Nutrici\u00f3n Salvador Zubir\u00e1n, Mexico City, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alyssa K.","family":"McGary","sequence":"additional","affiliation":[{"name":"Division of Clinical Trials and Biostatistics, Mayo Clinic, Phoenix, Arizona"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mazie","family":"Tsang","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, Mayo Clinic, Phoenix, Arizona"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana","family":"Almader-Douglas","sequence":"additional","affiliation":[{"name":"Medical Library, Mayo Clinic, Phoenix, Arizona"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose F.","family":"Leis","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, Mayo Clinic, Phoenix, Arizona"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew R.","family":"Buras","sequence":"additional","affiliation":[{"name":"Division of Clinical Trials and Biostatistics, Mayo Clinic, Rochester, Minnesota"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Talal","family":"Hilal","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, Mayo Clinic, Phoenix, Arizona"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"10","reference":[{"issue":"5","key":"coi240030r1","doi-asserted-by":"publisher","first-page":"432","DOI":"10.1056\/NEJMoa1817073","article-title":"Ibrutinib-rituximab or chemoimmunotherapy for chronic lymphocytic leukemia.","volume":"381","author":"Shanafelt","year":"2019","journal-title":"N Engl J Med"},{"issue":"10232","key":"coi240030r2","doi-asserted-by":"publisher","first-page":"1278","DOI":"10.1016\/S0140-6736(20)30262-2","article-title":"Acalabrutinib with or without obinutuzumab versus chlorambucil and obinutuzmab for treatment-naive chronic lymphocytic leukaemia (ELEVATE TN): a randomised, controlled, phase 3 trial.","volume":"395","author":"Sharman","year":"2020","journal-title":"Lancet"},{"issue":"8","key":"coi240030r3","doi-asserted-by":"publisher","first-page":"1031","DOI":"10.1016\/S1470-2045(22)00293-5","article-title":"Zanubrutinib versus bendamustine and rituximab in untreated chronic lymphocytic leukaemia and small lymphocytic lymphoma (SEQUOIA): a randomised, controlled, phase 3 trial.","volume":"23","author":"Tam","year":"2022","journal-title":"Lancet Oncol"},{"issue":"23","key":"coi240030r4","doi-asserted-by":"publisher","first-page":"2225","DOI":"10.1056\/NEJMoa1815281","article-title":"Venetoclax and obinutuzumab in patients with CLL and coexisting conditions.","volume":"380","author":"Fischer","year":"2019","journal-title":"N Engl J Med"},{"issue":"19","key":"coi240030r5","doi-asserted-by":"publisher","first-page":"1739","DOI":"10.1056\/NEJMoa2213093","article-title":"First-line venetoclax combinations in chronic lymphocytic leukemia.","volume":"388","author":"Eichhorst","year":"2023","journal-title":"N Engl J Med"},{"issue":"25","key":"coi240030r6","doi-asserted-by":"publisher","first-page":"2745","DOI":"10.1182\/blood-2017-09-806398","article-title":"iwCLL guidelines for diagnosis, indications for treatment, response assessment, and supportive management of CLL.","volume":"131","author":"Hallek","year":"2018","journal-title":"Blood"},{"issue":"8","key":"coi240030r7","doi-asserted-by":"publisher","first-page":"907","DOI":"10.1007\/s11864-023-01103-1","article-title":"Measurable residual disease in chronic lymphocytic leukemia: current understanding and evolving role in clinical practice.","volume":"24","author":"Rios-Olais","year":"2023","journal-title":"Curr Treat Options Oncol"},{"issue":"7","key":"coi240030r8","doi-asserted-by":"publisher","DOI":"10.1001\/jamaoncol.2017.0580","article-title":"Association of minimal residual disease with clinical outcome in pediatric and adult acute lymphoblastic leukemia: a meta-analysis.","volume":"3","author":"Berry","year":"2017","journal-title":"JAMA Oncol"},{"issue":"8","key":"coi240030r9","doi-asserted-by":"publisher","first-page":"1778","DOI":"10.1038\/s41375-018-0146-5","article-title":"Obinutuzumab plus bendamustine in previously untreated patients with CLL: a subgroup analysis of the GREEN study.","volume":"32","author":"Stilgenbauer","year":"2018","journal-title":"Leukemia"},{"issue":"12","key":"coi240030r10","doi-asserted-by":"publisher","first-page":"1101","DOI":"10.1056\/NEJMoa1313984","article-title":"Obinutuzumab plus chlorambucil in patients with CLL and coexisting conditions.","volume":"370","author":"Goede","year":"2014","journal-title":"N Engl J Med"},{"issue":"9","key":"coi240030r11","doi-asserted-by":"publisher","first-page":"2108","DOI":"10.3324\/haematol.2021.279012","article-title":"First-line treatment of chronic lymphocytic leukemia with ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab: final analysis of the randomized, phase III iLLUMINATE trial.","volume":"107","author":"Moreno","year":"2022","journal-title":"Haematologica"},{"issue":"4","key":"coi240030r12","doi-asserted-by":"publisher","first-page":"969","DOI":"10.1038\/s41375-018-0276-9","article-title":"Updated results from the phase 3 HELIOS study of ibrutinib, bendamustine, and rituximab in relapsed chronic lymphocytic leukemia\/small lymphocytic lymphoma.","volume":"33","author":"Fraser","year":"2019","journal-title":"Leukemia"},{"issue":"8","key":"coi240030r13","doi-asserted-by":"publisher","first-page":"839","DOI":"10.1182\/blood.2021015014","article-title":"Enduring undetectable MRD and updated outcomes in relapsed\/refractory CLL after fixed-duration venetoclax-rituximab.","volume":"140","author":"Seymour","year":"2022","journal-title":"Blood"},{"issue":"35","key":"coi240030r14","doi-asserted-by":"publisher","first-page":"5616","DOI":"10.1200\/JCO.2007.12.9098","article-title":"Alemtuzumab compared with chlorambucil as first-line therapy for chronic lymphocytic leukemia.","volume":"25","author":"Hillmen","year":"2007","journal-title":"J Clin Oncol"},{"issue":"26","key":"coi240030r15","doi-asserted-by":"publisher","first-page":"2517","DOI":"10.1056\/NEJMoa1812836","article-title":"Ibrutinib regimens versus chemoimmunotherapy in older patients with untreated CLL.","volume":"379","author":"Woyach","year":"2018","journal-title":"N Engl J Med"},{"key":"coi240030r16","doi-asserted-by":"publisher","first-page":"178","DOI":"10.1016\/j.jclinepi.2021.03.001","article-title":"The PRISMA 2020 statement: an updated guideline for reporting systematic reviews.","volume":"134","author":"Page","year":"2021","journal-title":"J Clin Epidemiol"},{"issue":"11","key":"coi240030r17","doi-asserted-by":"publisher","first-page":"3059","DOI":"10.1038\/s41375-021-01241-1","article-title":"Measurable residual disease in chronic lymphocytic leukemia: expert review and consensus recommendations.","volume":"35","author":"Wierda","year":"2021","journal-title":"Leukemia"},{"issue":"3","key":"coi240030r20","doi-asserted-by":"publisher","first-page":"1","DOI":"10.18637\/jss.v036.i03","article-title":"Conducting meta-analyses in R with the metafor package.","volume":"36","author":"Viechtbauer","year":"2010","journal-title":"J Stat Softw"},{"issue":"26","key":"coi240030r22","doi-asserted-by":"publisher","first-page":"2810","DOI":"10.1182\/blood.2020010146","article-title":"Measurable residual disease does not preclude prolonged progression-free survival in CLL treated with ibrutinib.","volume":"138","author":"Wang","year":"2021","journal-title":"Blood"},{"issue":"4","key":"coi240030r23","doi-asserted-by":"publisher","first-page":"e254","DOI":"10.1016\/S2352-3026(20)30433-6","article-title":"Ublituximab plus ibrutinib versus ibrutinib alone for patients with relapsed or refractory high-risk chronic lymphocytic leukaemia (GENUINE): a phase 3, multicentre, open-label, randomised trial.","volume":"8","author":"Sharman","year":"2021","journal-title":"Lancet Haematol"},{"issue":"21","key":"coi240030r24","doi-asserted-by":"publisher","first-page":"3689","DOI":"10.1200\/JCO.22.02283","article-title":"Impact of minimal residual disease on progression-free survival outcomes after fixed-duration ibrutinib-venetoclax versus chlorambucil-obinutuzumab in the GLOW study.","volume":"41","author":"Munir","year":"2023","journal-title":"J Clin Oncol"},{"issue":"36","key":"coi240030r25","doi-asserted-by":"publisher","first-page":"4049","DOI":"10.1200\/JCO.21.01181","article-title":"Minimal residual disease dynamics after venetoclax-obinutuzumab treatment: extended off-treatment follow-up from the randomized CLL14 study.","volume":"39","author":"Al-Sawaf","year":"2021","journal-title":"J Clin Oncol"},{"issue":"19","key":"coi240030r26","doi-asserted-by":"publisher","first-page":"1973","DOI":"10.1200\/JCO.2017.76.6840","article-title":"Venetoclax for patients with chronic lymphocytic leukemia with 17p deletion: results from the full population of a phase II pivotal trial.","volume":"36","author":"Stilgenbauer","year":"2018","journal-title":"J Clin Oncol"},{"issue":"1","key":"coi240030r27","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1002\/jrsm.1411","article-title":"Risk-of-bias visualization (robvis): an R package and Shiny web app for visualizing risk-of-bias assessments.","volume":"12","author":"McGuinness","year":"2021","journal-title":"Res Synth Methods"},{"issue":"7","key":"coi240030r28","doi-asserted-by":"publisher","first-page":"423","DOI":"10.1016\/j.clml.2019.03.014","article-title":"Minimal residual disease and survival outcomes in patients with chronic lymphocytic leukemia: a systematic review and meta-analysis.","volume":"19","author":"Molica","year":"2019","journal-title":"Clin Lymphoma Myeloma Leuk"},{"issue":"34","key":"coi240030r29","doi-asserted-by":"publisher","first-page":"3853","DOI":"10.1200\/JCO.21.00807","article-title":"Ibrutinib plus venetoclax for first-line treatment of chronic lymphocytic leukemia: primary analysis results from the minimal residual disease cohort of the randomized phase II CAPTIVATE study.","volume":"39","author":"Wierda","year":"2021","journal-title":"J Clin Oncol"},{"issue":"6","key":"coi240030r30","doi-asserted-by":"publisher","first-page":"818","DOI":"10.1016\/S1470-2045(22)00220-0","article-title":"Minimal residual disease-guided stop and start of venetoclax plus ibrutinib for patients with relapsed or refractory chronic lymphocytic leukaemia (HOVON141\/VISION): primary analysis of an open-label, randomised, phase 2 trial.","volume":"23","author":"Kater","year":"2022","journal-title":"Lancet Oncol"},{"issue":"4","key":"coi240030r31","doi-asserted-by":"publisher","first-page":"326","DOI":"10.1056\/NEJMoa2310063","article-title":"Chronic lymphocytic leukemia therapy guided by measurable residual disease.","volume":"390","author":"Munir","year":"2024","journal-title":"N Engl J Med"},{"issue":"24","key":"coi240030r32","doi-asserted-by":"publisher","first-page":"3727","DOI":"10.1182\/blood-2013-11-538116","article-title":"Eradication of bone marrow minimal residual disease may prompt early treatment discontinuation in CLL.","volume":"123","author":"Strati","year":"2014","journal-title":"Blood"},{"issue":"22","key":"coi240030r33","doi-asserted-by":"publisher","first-page":"1951","DOI":"10.1182\/blood.2019001077","article-title":"Minimal residual disease undetectable by next-generation sequencing predicts improved outcome in CLL after chemoimmunotherapy.","volume":"134","author":"Thompson","year":"2019","journal-title":"Blood"},{"key":"coi240030r18","unstructured":"Higgins? JP, Savovic? J, Page? MJ, Sterne? JA. Revised Cochrane risk-of-bias tool for randomized trials (RoB 2). Accessed October 31, 2023. https:\/\/www.riskofbias.info\/welcome\/rob-2-0-tool\/current-version-of-rob-2"},{"key":"coi240030r19","unstructured":"Sterne? J, Higgins? J, Reeves? B. Current version of ROBINS-I. Accessed November 1, 2023. https:\/\/www.riskofbias.info\/welcome\/home\/current-version-of-robins-i"},{"key":"coi240030r21","unstructured":"Foucher? Y, Le Borgne? F, Chatton? A, Sabathe? C. RISCA: causal inference and prediction in cohort-based analyses, version 1.0.4. R package documentation, 2023. Accessed November 15, 2023. https:\/\/rdrr.io\/cran\/RISCA"}],"container-title":["JAMA Oncology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/jamanetwork.com\/journals\/jamaoncology\/articlepdf\/2821029\/jamaoncology_riosolais_2024_oi_240030_1726602712.31074.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,9,19]],"date-time":"2024-09-19T16:34:45Z","timestamp":1726763685000},"score":1,"resource":{"primary":{"URL":"https:\/\/jamanetwork.com\/journals\/jamaoncology\/fullarticle\/2821029"}},"subtitle":["A Systematic Review and Meta-Analysis"],"short-title":[],"issued":{"date-parts":[[2024,9,1]]},"references-count":33,"journal-issue":{"issue":"9","published-print":{"date-parts":[[2024,9,1]]}},"URL":"https:\/\/doi.org\/10.1001\/jamaoncol.2024.2122","relation":{},"ISSN":["2374-2437"],"issn-type":[{"value":"2374-2437","type":"print"}],"subject":[],"published":{"date-parts":[[2024,9,1]]}}}