{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T04:51:41Z","timestamp":1789015901735,"version":"build-2803163510"},"reference-count":24,"publisher":"American Society of Hematology","issue":"22","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2022,12,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Undetectable measurable residual disease (uMRD) is achievable in patients with chronic lymphocytic leukemia (CLL) with the BCL2-inhibitor venetoclax alone or combined with the Bruton\u2019s tyrosine kinase inhibitor ibrutinib. This phase 2, multicenter, MRD-driven study was designed to discontinue treatment upon reaching uMRD4 (&amp;lt;10\u22124) in patients with relapsed\/refractory CLL receiving venetoclax monotherapy or after the addition of ibrutinib. Primary end point of the study was proportion of uMRD4 with venetoclax\u00a0\u00b1 ibrutinib. Secondary end points were overall response rate, partial response, complete response, progression-free survival, duration of response, overall survival, and safety of venetoclax\u00a0\u00b1 ibrutinib. Patients with uMRD4 at Cycle 12\u00a0Day 1 discontinued venetoclax. MRD+ patients added ibrutinib and continued both drugs up to Cycle 24 Day 28\/uMRD4\/progression\/toxicity. After Cycle 24 Day 28, MRD+ patients continued ibrutinib. Thirty-eight patients (29% with TP53 aberrations; 79% with unmutated IGHV) started venetoclax. Overall response rate with venetoclax was 36 (95%) of 38 patients (20 complete; 16 partial response). Seventeen patients (45%) with uMRD4 at Cycle 12 Day 1\u00a0discontinued venetoclax. Nineteen (55%) MRD+ subjects added ibrutinib. After a median of 7\u00a0months (range, 3-10 months) of combined treatment, 16 (84%) of 19 achieved uMRD4, thus stopping both drugs. Two MRD+ patients at Cycle 24 Day 28 continued ibrutinib until progression\/toxicity. After a median follow-up of 36.5 months, median progression-free survival was not reached; 10 patients progressed (4\u00a0restarted venetoclax, 3 without treatment need, 2 developed Richter transformation, and 1 dropped out). Seven (22%) of 32 patients remain uMRD4 after 3 years of follow-up. Neutropenia was the most frequent grade 3 to 4 adverse event; no grade 5 events occurred on study. This sequential MRD-guided approach led to uMRD4 in 33 (87%) of 38 patients, with venetoclax monotherapy or combined with ibrutinib, delivering treatment combination only in a fraction, and ultimately identifying the few patients benefiting from continuous therapy. This trial was registered at www.clinicaltrials.gov as # NCT04754035.<\/jats:p>","DOI":"10.1182\/blood.2022016901","type":"journal-article","created":{"date-parts":[[2022,8,3]],"date-time":"2022-08-03T19:06:12Z","timestamp":1659553572000},"page":"2348-2357","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":11,"title":["Minimal residual disease\u2013driven treatment intensification with sequential addition of ibrutinib to\u00a0venetoclax in\u00a0R\/R\u00a0CLL"],"prefix":"10.1182","volume":"140","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0844-0989","authenticated-orcid":false,"given":"Lydia","family":"Scarf\u00f2","sequence":"first","affiliation":[{"name":"1Strategic Research Program on Chronic Lymphocytic Leukemia (CLL), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ospedale San Raffaele, Milano, Italy"},{"name":"2Laboratory of B-cell Neoplasia, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ospedale San Raffaele, Milano, Italy"},{"name":"3Universit\u00e0 Vita Salute San Raffaele, Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Heltai","sequence":"additional","affiliation":[{"name":"2Laboratory of B-cell Neoplasia, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ospedale San Raffaele, Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisa","family":"Albi","sequence":"additional","affiliation":[{"name":"1Strategic Research Program on Chronic Lymphocytic Leukemia (CLL), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ospedale San Raffaele, Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eloise","family":"Scarano","sequence":"additional","affiliation":[{"name":"1Strategic Research Program on Chronic Lymphocytic Leukemia (CLL), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ospedale San Raffaele, Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luana","family":"Schiattone","sequence":"additional","affiliation":[{"name":"1Strategic Research Program on Chronic Lymphocytic Leukemia (CLL), Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ospedale San Raffaele, Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lucia","family":"Farina","sequence":"additional","affiliation":[{"name":"4Division of Hematology, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Nazionale dei Tumori, Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Riccardo","family":"Moia","sequence":"additional","affiliation":[{"name":"5Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Deodato","sequence":"additional","affiliation":[{"name":"6Department of Hematology, Niguarda Cancer Center, Niguarda Hospital, Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Ferrario","sequence":"additional","affiliation":[{"name":"7Hematology Unit, Azienda Socio Sanitaria Territoriale (ASST) dei Sette Laghi-Ospedale di Circolo di Varese, Varese, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marina","family":"Motta","sequence":"additional","affiliation":[{"name":"8Department of Hematology, Azienda Socio Sanitaria Territoriale (ASST) Spedali Civili di Brescia, Brescia, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gianluigi","family":"Reda","sequence":"additional","affiliation":[{"name":"9Hematology Unit, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Ca' Granda Ospedale Maggiore Policlinico, Milano, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosaria","family":"Sancetta","sequence":"additional","affiliation":[{"name":"10Hematology Unit, Ospedale dell\u2019Angelo, Venezia-Mestre, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marta","family":"Coscia","sequence":"additional","affiliation":[{"name":"11Division of Hematology, Azienda Ospedaliera Universitaria (A.O.U.) 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