# Relapsed or refractory chronic lymphocytic leukaemia

Source: https://onco.cc/cancers/cll-relapsed/  
OnCo record `cll-relapsed` (Cancer). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

The 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).

Double-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.

## Fields

- Kind: Cancer
- Last checked: 2026-09-17
- Also known as: Relapsed CLL; Refractory CLL; Double-refractory CLL (after BTK and BCL-2 inhibitors); CLL after BTK inhibitor failure
- Tags: subtype-page
- 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

## Sections of this record

The page is a hub with ten sections in reading order; large sections have their own page. The same plan as JSON: https://onco.cc/api/v1/cancers/cll-relapsed/sections.json

- Overview (on the hub): The TL;DR, the family this cancer belongs to, the organ, who gets it and what the state of the art is. https://onco.cc/cancers/cll-relapsed/#overview [3 state-of-the-art points]
- Types and stages (on the hub): Anatomy, the subtypes and how they differ, how it is staged, and where advanced disease spreads. https://onco.cc/cancers/cll-relapsed/#what-it-is [6 subtypes]
- Symptoms and diagnosis (on the hub): How this cancer shows itself, how the diagnosis is confirmed, and the biomarkers clinicians test for. https://onco.cc/cancers/cll-relapsed/#finding-it [7 biomarkers]
- Treatment (on the hub): The standard of care by setting, the medicines, surgery and radiotherapy named in it, and the regimens behind them. https://onco.cc/cancers/cll-relapsed/#treating-it [3 settings, 3 decisions with options]
- Trials and papers (on the hub): Trials recruiting now, the landmark trials, the trials held by this cancer's subtypes, the key papers and what they mean, the latest literature, and the milestones year by year. https://onco.cc/cancers/cll-relapsed/#evidence [30 trials, 1 key paper, 6 milestones]
- Biology and targets (on the hub): The molecular landscape: the targets and how often each appears, the pathways, the mechanics stages and the preclinical models. https://onco.cc/cancers/cll-relapsed/#science [5 targets, 2 pathways]
- Countries and centres (own page): Cases by country, the UK and NHS pathway and other country lenses, the expert centres with trials on record, and the centres named on this cancer's subtypes. https://onco.cc/cancers/cll-relapsed/where-you-are/
- Decisions and support (on the hub): The decisions you may face, the aids that walk through them, the warnings on record, the first sixty days and the questions to ask. https://onco.cc/cancers/cll-relapsed/#living-with-it [18 questions, 6 red cards]
- Pipeline and open problems (own page): Everything in development, the medicines held by this cancer's subtypes, the open problems and what is being done about them, the roadmaps, and what changed on this record. https://onco.cc/cancers/cll-relapsed/coming/ [11 medicines, 28 trials, 3 open problems]
- Data (own page): Every connected record, the notes, the JSON, Markdown and RDF twins, and where the record came from and when it was checked. https://onco.cc/cancers/cll-relapsed/data/ [74 connected records]

## Standard of care

- Relapse after a BTK inhibitor: Venetoclax plus rituximab for two years (MURANO) or venetoclax-obinutuzumab; pirtobrutinib after covalent BTK inhibitor failure (BRUIN CLL-321). ([Venetoclax](https://onco.cc/drugs/venetoclax/), [Rituximab](https://onco.cc/drugs/rituximab/), [Obinutuzumab](https://onco.cc/drugs/obinutuzumab/), [Pirtobrutinib](https://onco.cc/drugs/pirtobrutinib/), [BRUIN CLL-321](https://onco.cc/trials/bruin-cll-321/))
- Relapse after venetoclax: Acalabrutinib or zanubrutinib (ALPINE) continuously, or ibrutinib; venetoclax retreatment if the prior remission lasted a year or more. ([Acalabrutinib](https://onco.cc/drugs/acalabrutinib/), [Zanubrutinib](https://onco.cc/drugs/zanubrutinib/), [Ibrutinib](https://onco.cc/drugs/ibrutinib/), [Venetoclax](https://onco.cc/drugs/venetoclax/), [ALPINE](https://onco.cc/trials/alpine/), [RESONATE](https://onco.cc/trials/resonate/))
- Double-refractory after BTK inhibitor and venetoclax: Pirtobrutinib; lisocabtagene maraleucel CAR-T (TRANSCEND CLL 004); idelalisib-rituximab; clinical trials of BTK degraders, sonrotoclax and bispecifics; allogeneic transplant in fit young patients. ([Pirtobrutinib](https://onco.cc/drugs/pirtobrutinib/), [Lisocabtagene maraleucel](https://onco.cc/drugs/lisocabtagene-maraleucel/), [TRANSCEND CLL 004](https://onco.cc/trials/transcend-cll-004/), [Idelalisib](https://onco.cc/drugs/idelalisib/), [Rituximab](https://onco.cc/drugs/rituximab/), [Sonrotoclax](https://onco.cc/drugs/sonrotoclax/), [Nemtabrutinib](https://onco.cc/drugs/nemtabrutinib/), [Allogeneic stem cell transplantation](https://onco.cc/technologies/allogeneic-hsct/))

## State of the art

- 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.

## Open problems

- 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.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Chronic_lymphocytic_leukemia
- Wikipedia: https://en.wikipedia.org/wiki/Chronic_lymphocytic_leukemia
- NCCN Guidelines: CLL/SLL: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1478

## Connected records

- cancers: [Chronic lymphocytic leukaemia](https://onco.cc/cancers/cll/), [Chronic lymphocytic leukaemia, first treatment](https://onco.cc/cancers/cll-treatment-naive/), [Richter transformation of chronic lymphocytic leukaemia](https://onco.cc/cancers/richter-transformation-cll/)
- technologies: [Allogeneic stem cell transplantation](https://onco.cc/technologies/allogeneic-hsct/), [BCL-2 inhibitors](https://onco.cc/technologies/bcl2-inhibitors/), [CAR-T cell therapy](https://onco.cc/technologies/car-t/), [Multiparameter flow cytometry MRD](https://onco.cc/technologies/flow-cytometry-mrd/)
- targets: [BCL-2](https://onco.cc/targets/bcl2/), [BTK (Bruton tyrosine kinase)](https://onco.cc/targets/btk/), [CD19](https://onco.cc/targets/cd19/), [CD20](https://onco.cc/targets/cd20/)
- pathways: [B-cell receptor / BTK signalling (to NF-κB)](https://onco.cc/pathways/bcr-signalling/), [Intrinsic apoptosis (BCL-2 family)](https://onco.cc/pathways/apoptosis-bcl2/)
- terms: [BTK C481S, PLCG2 and BCL2 G101V resistance mutations](https://onco.cc/terms/btki-bcl2i-resistance-mutations/), [del(17p) / TP53 aberration in CLL](https://onco.cc/terms/del17p-tp53/), [Drug resistance (primary and acquired)](https://onco.cc/terms/resistance/), [Richter transformation](https://onco.cc/terms/richter-transformation/), [Undetectable MRD (uMRD / MRD-negative)](https://onco.cc/terms/umrd/)
- trials: [A Study Evaluating the Efficacy and Safety of Pirtobrutinib in Participants With Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma](https://onco.cc/trials/nct06588478/), [A Study of Acalabrutinib vs Investigator's Choice of Idelalisib Plus Rituximab or Bendamustine Plus Rituximab in R/R CLL](https://onco.cc/trials/nct02970318/), [A Study of ACP-196 (Acalabrutinib) in Subjects With Relapsed/Refractory CLL and Intolerant of Ibrutinib Therapy](https://onco.cc/trials/nct02717611/), [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](https://onco.cc/trials/nct06970743/), [A Study of DZD8586 Versus Investigator's Choice in r/r CLL/SLL (TAI-SHAN6)](https://onco.cc/trials/tai-shan6/), [A Study of GNC-035 in Relapsed or Refractory Chronic Lymphocytic Leukemia and Other Hematological Malignancies](https://onco.cc/trials/nct05944978/), [A Study of Lacutoclax (LP-108) in Patients With Relapsed/Refractory CLL/SLL](https://onco.cc/trials/nct07609823/), [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).](https://onco.cc/trials/nct05947851/), [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)](https://onco.cc/trials/nct07221500/), [A Study of Venetoclax in Participants With Relapsed or Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma](https://onco.cc/trials/nct02966756/), [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](https://onco.cc/trials/nct06973187/), [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)](https://onco.cc/trials/nct06943872/), [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)](https://onco.cc/trials/nct04965493/), [ALPINE](https://onco.cc/trials/alpine/), [BELLWAVE-011](https://onco.cc/trials/bellwave-011/), [BRUIN CLL-321](https://onco.cc/trials/bruin-cll-321/), [CaDAnCe-304](https://onco.cc/trials/cadance-304/), [DZD8586 in Patients With Relapsed or Refractory CLL/SLL (TAI-SHAN8)](https://onco.cc/trials/nct06539182/), [MURANO](https://onco.cc/trials/murano/), [RESONATE](https://onco.cc/trials/resonate/), [ROCKET-CLL Global Phase 3 Study: Rocbrutinib vs Pirtobrutinib in cBTKi-Pretreated R/R CLL/SLL](https://onco.cc/trials/nct07342478/), [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)](https://onco.cc/trials/nct04416984/), [Safety and Efficacy Study of Epcoritamab in Subjects With Relapsed/Refractory Chronic Lymphocytic Leukemia and Richter's Syndrome](https://onco.cc/trials/nct04623541/), [Study of Acalabrutinib (ACP-196) Versus Ibrutinib in Previously Treated Participants With High Risk Chronic Lymphocytic Leukemia (CLL)](https://onco.cc/trials/nct02477696/), [Study of APG-2575 in Patients With Relapsed/Refractory CLL/SLL](https://onco.cc/trials/nct05147467/), [Study of APG2575 Single Agent and Combination Therapy in Patients With Relapsed/Refractory CLL/SLL](https://onco.cc/trials/nct04494503/), [Study of BGB-11417 in Participants With Relapsed or Refractory Chronic Lymphocytic Leukemia or Small Lymphocytic Lymphoma](https://onco.cc/trials/nct05479994/), [Study of NX-5948 Versus Pirtobrutinib in R/R CLL/SLL](https://onco.cc/trials/nct07516093/), [Testing the Effectiveness of the Anti-cancer Drug, Mirdametinib, in Treating Relapsed, Refractory Chronic Lymphocytic Leukemia](https://onco.cc/trials/nct07061951/), [TRANSCEND CLL 004](https://onco.cc/trials/transcend-cll-004/)
- key papers: [MURANO: two years of venetoclax plus rituximab versus chemo-immunotherapy in relapsed CLL](https://onco.cc/key-papers/paper-murano-venetoclax-rituximab-nejm-2018/)
- drugs: [Acalabrutinib](https://onco.cc/drugs/acalabrutinib/), [Ibrutinib](https://onco.cc/drugs/ibrutinib/), [Idelalisib](https://onco.cc/drugs/idelalisib/), [Lisocabtagene maraleucel](https://onco.cc/drugs/lisocabtagene-maraleucel/), [Nemtabrutinib](https://onco.cc/drugs/nemtabrutinib/), [Obinutuzumab](https://onco.cc/drugs/obinutuzumab/), [Pirtobrutinib](https://onco.cc/drugs/pirtobrutinib/), [Rituximab](https://onco.cc/drugs/rituximab/), [Sonrotoclax](https://onco.cc/drugs/sonrotoclax/), [Venetoclax](https://onco.cc/drugs/venetoclax/), [Zanubrutinib](https://onco.cc/drugs/zanubrutinib/)
- biomarkers: [TP53 mutation and del(17p)](https://onco.cc/biomarkers/tp53-del17p/)

---
JSON: https://onco.cc/api/v1/entities/cll-relapsed.json