{"entity":{"id":"cll-relapsed","kind":"cancer","name":"Relapsed or refractory chronic lymphocytic leukaemia","aka":["Relapsed CLL","Refractory CLL","Double-refractory CLL (after BTK and BCL-2 inhibitors)","CLL after BTK inhibitor failure"],"tldr":"When chronic lymphocytic leukaemia returns, the usual move is to switch drug class: venetoclax-based therapy after a BTK inhibitor, or a BTK inhibitor after venetoclax. Pirtobrutinib (BRUIN) works after the older BTK inhibitors fail, and CAR-T is approved for patients who have run out of both classes.","summary":"Relapse is usually slow and treatment resumes only when iwCLL criteria are met again. The regimen depends on what was given first and why it stopped: progression on a covalent BTK inhibitor usually means a BTK C481 mutation or PLCG2 mutation and calls for venetoclax-based therapy or the non-covalent inhibitor pirtobrutinib; intolerance to one covalent BTK inhibitor can be managed by switching to another (ALPINE found zanubrutinib superior to ibrutinib in relapsed disease, progression-free survival hazard ratio 0.65, with less atrial fibrillation, 5.2 versus 13.3 percent); relapse a year or more after fixed-duration venetoclax can be treated with venetoclax again; TP53 aberrant disease and complex karyotype shorten every remission.\n\nThe landmark trials each defined a setting. RESONATE (2014) established ibrutinib against ofatumumab in relapsed disease (hazard ratio 0.22 for progression, median 44.1 versus 8.1 months on long follow-up). MURANO (2018) established two years of venetoclax-rituximab against bendamustine-rituximab, with two-year progression-free survival of 84.9 versus 36.3 percent and a survival gain, the first fixed-duration targeted regimen. BRUIN CLL-321 (2024) showed pirtobrutinib beat investigator's choice of idelalisib-rituximab or bendamustine-rituximab after covalent BTK inhibitor failure, and pirtobrutinib was approved in 2023 for patients previously treated with both a BTK and a BCL-2 inhibitor. Lisocabtagene maraleucel, a CD19 CAR-T, was approved in 2024 for the same double-exposed group after TRANSCEND CLL 004 (complete remission in about a fifth, undetectable MRD in the blood in two thirds).\n\nDouble-refractory disease after covalent BTK inhibitor and venetoclax remains the unmet need: median survival is short, and pirtobrutinib responses last about a year and a half. BTK degraders (bexobrutideg, NX-5948), the next BCL-2 inhibitor sonrotoclax, the non-covalent inhibitor nemtabrutinib, bispecific antibodies (epcoritamab) and allogeneic transplant in the young are the options being tested, and about one in twenty relapses proves to be Richter transformation rather than CLL.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Chronic_lymphocytic_leukemia","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Chronic_lymphocytic_leukemia"},{"label":"NCCN Guidelines: CLL/SLL","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1478"}],"tags":["subtype-page"],"related":["cll-treatment-naive","richter-transformation-cll"],"cancers":[],"sections":[],"technologies":["car-t","bcl2-inhibitors","flow-cytometry-mrd"],"targets":["btk","bcl2","cd19","cd20"],"drugs":[],"companies":[],"institutions":[],"pathways":["bcr-signalling","apoptosis-bcl2"],"terms":["del17p-tp53","resistance","umrd","richter-transformation","btki-bcl2i-resistance-mutations"],"trials":["murano"],"people":[],"bottlenecks":[],"keyPapers":["paper-murano-venetoclax-rituximab-nejm-2018"],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"Most patients treated for chronic lymphocytic leukaemia relapse eventually, though often after many years; the small group whose disease resists both a BTK inhibitor and venetoclax has the shortest survival and the most active research.","subtypes":["Relapse after chemoimmunotherapy (BTK inhibitor or venetoclax-based)","Relapse after fixed-duration venetoclax (retreatment or BTK inhibitor)","Progression on a covalent BTK inhibitor (BTK C481 or PLCG2 mutation)","Intolerance to a covalent BTK inhibitor (switch agent)","Double-refractory CLL after BTK inhibitor and venetoclax (pirtobrutinib, CAR-T, trials)","Relapsed CLL with del(17p) or TP53 mutation"],"biomarkers":["BTK C481S and PLCG2 resistance mutations","BCL2 G101V mutation","del(17p) and TP53 mutation re-tested at relapse","Complex karyotype","IGHV status","Time since fixed-duration therapy ended","Biopsy of a rapidly growing node to exclude Richter transformation"],"standardOfCare":[{"setting":"Relapse after a BTK inhibitor","approach":"Venetoclax plus rituximab for two years (MURANO) or venetoclax-obinutuzumab; pirtobrutinib after covalent BTK inhibitor failure (BRUIN CLL-321).","refs":["venetoclax","rituximab","obinutuzumab","pirtobrutinib","bruin-cll-321"],"guideline":{"version":"NCCN Guidelines: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1478"}},{"setting":"Relapse after venetoclax","approach":"Acalabrutinib or zanubrutinib (ALPINE) continuously, or ibrutinib; venetoclax retreatment if the prior remission lasted a year or more.","refs":["acalabrutinib","zanubrutinib","ibrutinib","venetoclax","alpine","resonate"],"guideline":{"version":"NCCN Guidelines: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1478"}},{"setting":"Double-refractory after BTK inhibitor and venetoclax","approach":"Pirtobrutinib; lisocabtagene maraleucel CAR-T (TRANSCEND CLL 004); idelalisib-rituximab; clinical trials of BTK degraders, sonrotoclax and bispecifics; allogeneic transplant in fit young patients.","refs":["pirtobrutinib","lisocabtagene-maraleucel","transcend-cll-004","idelalisib","rituximab","sonrotoclax","nemtabrutinib","allogeneic-hsct"],"guideline":{"version":"NCCN Guidelines: Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1478"}}],"stateOfArt":["Class switching between BTK inhibitors and venetoclax gives most patients years more control.","Pirtobrutinib overcomes the resistance mutations that stop covalent BTK inhibitors, and CAR-T is approved for double-refractory disease.","BTK degraders and the next BCL-2 inhibitor are in phase 3 for the double-refractory group."],"history":[{"year":2014,"title":"RESONATE: ibrutinib beats ofatumumab in relapsed CLL; idelalisib approved","refs":["resonate","ibrutinib","idelalisib"]},{"year":2016,"title":"Venetoclax approved for relapsed del(17p) CLL","refs":["venetoclax"]},{"year":2018,"title":"MURANO: two years of venetoclax-rituximab beats chemoimmunotherapy","refs":["venetoclax","rituximab"]},{"year":2022,"title":"ALPINE: zanubrutinib beats ibrutinib head to head","refs":["alpine","zanubrutinib","ibrutinib"]},{"year":2023,"title":"Pirtobrutinib approved after BTK and BCL-2 inhibitor failure","refs":["pirtobrutinib"]},{"year":2024,"title":"BRUIN CLL-321 reads out; lisocabtagene maraleucel approved for double-refractory CLL","refs":["bruin-cll-321","lisocabtagene-maraleucel","transcend-cll-004"]}],"pipeline":["pirtobrutinib","sonrotoclax","nemtabrutinib","lisocabtagene-maraleucel","bellwave-011","cadance-304"],"openProblems":["Double-refractory disease after BTK inhibitor and venetoclax has no durable option.","Whether venetoclax retreatment works as well the second time, and after how long an interval.","Distinguishing CLL progression from Richter transformation early enough."],"parent":"cll"},"route":"/cancers/cll-relapsed/","neighbours":{"cancer":[{"id":"cll","kind":"cancer","name":"Chronic lymphocytic leukaemia","route":"/cancers/cll/"},{"id":"cll-treatment-naive","kind":"cancer","name":"Chronic lymphocytic leukaemia, first treatment","route":"/cancers/cll-treatment-naive/"},{"id":"richter-transformation-cll","kind":"cancer","name":"Richter transformation of chronic lymphocytic leukaemia","route":"/cancers/richter-transformation-cll/"}],"technology":[{"id":"allogeneic-hsct","kind":"technology","name":"Allogeneic stem cell transplantation","route":"/technologies/allogeneic-hsct/"},{"id":"bcl2-inhibitors","kind":"technology","name":"BCL-2 inhibitors","route":"/technologies/bcl2-inhibitors/"},{"id":"car-t","kind":"technology","name":"CAR-T cell therapy","route":"/technologies/car-t/"},{"id":"flow-cytometry-mrd","kind":"technology","name":"Multiparameter flow cytometry MRD","route":"/technologies/flow-cytometry-mrd/"}],"target":[{"id":"bcl2","kind":"target","name":"BCL-2","route":"/targets/bcl2/"},{"id":"btk","kind":"target","name":"BTK (Bruton tyrosine kinase)","route":"/targets/btk/"},{"id":"cd19","kind":"target","name":"CD19","route":"/targets/cd19/"},{"id":"cd20","kind":"target","name":"CD20","route":"/targets/cd20/"}],"pathway":[{"id":"bcr-signalling","kind":"pathway","name":"B-cell receptor / BTK signalling (to NF-κB)","route":"/pathways/bcr-signalling/"},{"id":"apoptosis-bcl2","kind":"pathway","name":"Intrinsic apoptosis (BCL-2 family)","route":"/pathways/apoptosis-bcl2/"}],"term":[{"id":"btki-bcl2i-resistance-mutations","kind":"term","name":"BTK C481S, PLCG2 and BCL2 G101V resistance mutations","route":"/terms/btki-bcl2i-resistance-mutations/"},{"id":"del17p-tp53","kind":"term","name":"del(17p) / TP53 aberration in CLL","route":"/terms/del17p-tp53/"},{"id":"resistance","kind":"term","name":"Drug resistance (primary and acquired)","route":"/terms/resistance/"},{"id":"richter-transformation","kind":"term","name":"Richter transformation","route":"/terms/richter-transformation/"},{"id":"umrd","kind":"term","name":"Undetectable MRD (uMRD / MRD-negative)","route":"/terms/umrd/"}],"trial":[{"id":"nct06588478","kind":"trial","name":"A Study Evaluating the Efficacy and Safety of Pirtobrutinib in Participants With Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma","route":"/trials/nct06588478/"},{"id":"nct02970318","kind":"trial","name":"A Study of Acalabrutinib vs Investigator's Choice of Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in R/R CLL","route":"/trials/nct02970318/"},{"id":"nct02717611","kind":"trial","name":"A Study of ACP-196 (Acalabrutinib) in Subjects With Relapsed/Refractory CLL and Intolerant of Ibrutinib Therapy","route":"/trials/nct02717611/"},{"id":"nct06970743","kind":"trial","name":"A Study of BGB-16673 Compared to Investigator's Choice in Participants With Relapsed/Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma Previously Exposed to Covalent Bruton Tyrosine Kinase (BTK) Inhibitors","route":"/trials/nct06970743/"},{"id":"tai-shan6","kind":"trial","name":"A Study of DZD8586 Versus Investigator's Choice in r/r CLL/SLL (TAI-SHAN6)","route":"/trials/tai-shan6/"},{"id":"nct05944978","kind":"trial","name":"A Study of GNC-035 in Relapsed or Refractory Chronic Lymphocytic Leukemia and Other Hematological Malignancies","route":"/trials/nct05944978/"},{"id":"nct07609823","kind":"trial","name":"A Study of Lacutoclax (LP-108) in Patients With Relapsed/Refractory CLL/SLL","route":"/trials/nct07609823/"},{"id":"nct05947851","kind":"trial","name":"A Study of Nemtabrutinib Plus Venetoclax vs Venetoclax + Rituximab (VR) in Second-line (2L) + Relapsed/Refractory (R/R) Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL) (MK-1026-010/BELLWAVE-010).","route":"/trials/nct05947851/"},{"id":"nct07221500","kind":"trial","name":"A Study of NX-5948 in Adults With CLL/SLL Previously Treated With a Bruton's Tyrosine Kinase Inhibitor and a B-cell Lymphoma-2 Inhibitor (DAYBreak CLL-201)","route":"/trials/nct07221500/"},{"id":"nct02966756","kind":"trial","name":"A Study of Venetoclax in Participants With Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma","route":"/trials/nct02966756/"},{"id":"nct06973187","kind":"trial","name":"A Study to Evaluate the Safety and Efficacy of Tacabrutideg (BGB-16673) Compared to Pirtobrutinib in Adults With Relapsed/Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma","route":"/trials/nct06973187/"},{"id":"nct06943872","kind":"trial","name":"A Study to Investigate Progression-Free Survival With Sonrotoclax Plus Obinutuzumab Or Sonrotoclax Plus Rituximab Compared With Venetoclax Plus Rituximab Treatment In Patients With Relapsed and/or Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CELESTIAL-RRCLL)","route":"/trials/nct06943872/"},{"id":"nct04965493","kind":"trial","name":"A Trial of Pirtobrutinib (LOXO-305) Plus Venetoclax and Rituximab (PVR) Versus Venetoclax and Rituximab (VR) in Previously Treated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma (CLL/SLL)","route":"/trials/nct04965493/"},{"id":"alpine","kind":"trial","name":"ALPINE","route":"/trials/alpine/"},{"id":"bellwave-011","kind":"trial","name":"BELLWAVE-011","route":"/trials/bellwave-011/"},{"id":"bruin-cll-321","kind":"trial","name":"BRUIN CLL-321","route":"/trials/bruin-cll-321/"},{"id":"cadance-304","kind":"trial","name":"CaDAnCe-304","route":"/trials/cadance-304/"},{"id":"nct06539182","kind":"trial","name":"DZD8586 in Patients With Relapsed or Refractory CLL/SLL (TAI-SHAN8)","route":"/trials/nct06539182/"},{"id":"murano","kind":"trial","name":"MURANO","route":"/trials/murano/"},{"id":"resonate","kind":"trial","name":"RESONATE","route":"/trials/resonate/"},{"id":"nct07342478","kind":"trial","name":"ROCKET-CLL Global Phase 3 Study: Rocbrutinib vs Pirtobrutinib in cBTKi-Pretreated R/R CLL/SLL","route":"/trials/nct07342478/"},{"id":"nct04416984","kind":"trial","name":"Safety and Efficacy of ALLO-501A Anti-CD19 Allogeneic CAR T Cells in Adults With Relapsed/Refractory Large B Cell Lymphoma, Chronic Lymphocytic Leukemia and Small Lymphocytic Lymphoma (ALPHA2)","route":"/trials/nct04416984/"},{"id":"nct04623541","kind":"trial","name":"Safety and Efficacy Study of Epcoritamab in Subjects With Relapsed/Refractory Chronic Lymphocytic Leukemia and Richter's Syndrome","route":"/trials/nct04623541/"},{"id":"nct02477696","kind":"trial","name":"Study of Acalabrutinib (ACP-196) Versus Ibrutinib in Previously Treated Participants With High Risk Chronic Lymphocytic Leukemia (CLL)","route":"/trials/nct02477696/"},{"id":"nct05147467","kind":"trial","name":"Study of APG-2575 in Patients With Relapsed/Refractory CLL/SLL","route":"/trials/nct05147467/"},{"id":"nct04494503","kind":"trial","name":"Study of APG2575 Single Agent and Combination Therapy in Patients With Relapsed/Refractory CLL/SLL","route":"/trials/nct04494503/"},{"id":"nct05479994","kind":"trial","name":"Study of BGB-11417 in Participants With Relapsed or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma","route":"/trials/nct05479994/"},{"id":"nct07516093","kind":"trial","name":"Study of NX-5948 Versus Pirtobrutinib in R/R CLL/SLL","route":"/trials/nct07516093/"},{"id":"nct07061951","kind":"trial","name":"Testing the Effectiveness of the Anti-cancer Drug, Mirdametinib, in Treating Relapsed, Refractory Chronic Lymphocytic Leukemia","route":"/trials/nct07061951/"},{"id":"transcend-cll-004","kind":"trial","name":"TRANSCEND CLL 004","route":"/trials/transcend-cll-004/"}],"paper":[{"id":"paper-murano-venetoclax-rituximab-nejm-2018","kind":"paper","name":"MURANO: two years of venetoclax plus rituximab versus chemo-immunotherapy in relapsed CLL","route":"/key-papers/paper-murano-venetoclax-rituximab-nejm-2018/"}],"drug":[{"id":"acalabrutinib","kind":"drug","name":"Acalabrutinib","route":"/drugs/acalabrutinib/"},{"id":"ibrutinib","kind":"drug","name":"Ibrutinib","route":"/drugs/ibrutinib/"},{"id":"idelalisib","kind":"drug","name":"Idelalisib","route":"/drugs/idelalisib/"},{"id":"lisocabtagene-maraleucel","kind":"drug","name":"Lisocabtagene maraleucel","route":"/drugs/lisocabtagene-maraleucel/"},{"id":"nemtabrutinib","kind":"drug","name":"Nemtabrutinib","route":"/drugs/nemtabrutinib/"},{"id":"obinutuzumab","kind":"drug","name":"Obinutuzumab","route":"/drugs/obinutuzumab/"},{"id":"pirtobrutinib","kind":"drug","name":"Pirtobrutinib","route":"/drugs/pirtobrutinib/"},{"id":"rituximab","kind":"drug","name":"Rituximab","route":"/drugs/rituximab/"},{"id":"sonrotoclax","kind":"drug","name":"Sonrotoclax","route":"/drugs/sonrotoclax/"},{"id":"venetoclax","kind":"drug","name":"Venetoclax","route":"/drugs/venetoclax/"},{"id":"zanubrutinib","kind":"drug","name":"Zanubrutinib","route":"/drugs/zanubrutinib/"}],"biomarker":[{"id":"tp53-del17p","kind":"biomarker","name":"TP53 mutation and del(17p)","route":"/biomarkers/tp53-del17p/"}]}}