{"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":[],"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"],"trials":[],"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 poorest outlook 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":{"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":"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/"}],"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/"}],"trial":[{"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":"resonate","kind":"trial","name":"RESONATE","route":"/trials/resonate/"},{"id":"transcend-cll-004","kind":"trial","name":"TRANSCEND CLL 004","route":"/trials/transcend-cll-004/"}],"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/"}],"cancer":[{"id":"cll","kind":"cancer","name":"Chronic lymphocytic leukaemia","route":"/cancers/cll/"}]}}