Relapsed or refractory chronic lymphocytic leukaemia
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.
Overview
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.
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.
Red cards
From the labels and guidelines behind the standard of care. Your team's thresholds win.- Emergency services nowMajor bleeding
Blood in stool or urine, vomiting blood, a bleed that will not stop, or a severe headache; fatal bleeding events have occurred and the labels advise considering the risk around surgery and with blood thinners.
- Emergency services nowTumour lysis syndrome
Nausea, vomiting, muscle cramps, palpitations, seizures, confusion or passing much less urine in the first days of a new dose; the label requires hydration, anti-hyperuricaemic drugs and blood tests around each ramp-up step.
- Emergency services nowCytokine release syndrome
Fever of 38 C or higher is grade 1 CRS; fever with low blood pressure, fast heartbeat, breathlessness or low oxygen is grade 2 or higher. The labels carry a boxed warning and say to report fever immediately.
- Check before combiningAcalabrutinib with Idelalisib: major interaction
CYP3A4: Idelalisib (strong inhibitor) raises Acalabrutinib exposure (sensitive substrate).. Avoid strong inhibitors; if short-term use is unavoidable, interrupt acalabrutinib. With a moderate inhibitor, reduce to 100 mg once daily.
- Check before combiningIbrutinib with Idelalisib: major interaction
CYP3A4: Idelalisib (strong inhibitor) raises Ibrutinib exposure (sensitive substrate).. Avoid strong inhibitors; with posaconazole or voriconazole reduce to 140 mg (or lower per label table); with moderate inhibitors reduce to 280 mg.
- Check before combiningVenetoclax with Idelalisib: major interaction
CYP3A4: Idelalisib (strong inhibitor) raises Venetoclax exposure (sensitive substrate).. Contraindicated with strong inhibitors during CLL ramp-up (tumour lysis). At steady state reduce by at least 75% with a strong inhibitor (400 mg to 100 mg; with posaconazole 70 mg) and by 50% with a moderate inhibitor. In AML with azoles: 100 mg (posaconazole) or 200 mg (voriconazole, fluconazole 50% reduction).
See all on the product pages:AcalabrutinibIbrutinibIdelalisibLisocabtagene maraleucelNemtabrutinibPirtobrutinibSonrotoclaxVenetoclaxZanubrutinib·Printable cards in the navigator
Anatomy and lymph node drainage
- Bone marrow (leukaemia, MDS, MPN, myeloma)
- Lymph node germinal centre (lymphomas)
- Spleen
- Blood (leukaemic phase)
- Lytic bone lesions (myeloma)
- Skin and extranodal sites
- Nodes: cervical
- Nodes: axillary
- Nodes: mediastinal
- Nodes: para-aortic and mesenteric
- Nodes: inguinal
Leukaemias, myeloma and MDS live in the marrow and blood; lymphomas grow in lymph nodes and spleen. The node stations are the disease map, not a route of spread, and staging counts them.
- Bone marrow (leukaemia, MDS, MPN, myeloma)Relapsed CLL with del(17p) or TP53 mutation
- Lymph node germinal centre (lymphomas)
- Spleen
- Blood (leukaemic phase)Double-refractory CLL after BTK inhibitor and venetoclax (pirtobrutinib, CAR-T, trials) · Relapsed CLL with del(17p) or TP53 mutation
- Lytic bone lesions (myeloma)
- Skin and extranodal sites
- cervical
- axillary
- mediastinal
- para-aortic and mesenteric
- inguinal
In lymphoma the node stations are the disease itself; staging (Ann Arbor / Lugano) counts how many regions and sides of the diaphragm are involved.
Same organ: Marginal zone lymphoma, Cutaneous T-cell lymphoma (mycosis fungoides and Sezary syndrome), Primary mediastinal (thymic) large B-cell lymphoma, Leukaemia (all types), Acute myeloid leukaemia, Acute lymphoblastic leukaemia, Chronic lymphocytic leukaemia, Chronic myeloid leukaemia (CML), Diffuse large B-cell lymphoma, Follicular lymphoma, Hodgkin lymphoma, Mantle cell lymphoma, Multiple myeloma, Non-Hodgkin lymphoma (all types), Myelodysplastic syndromes / neoplasms (MDS), Myeloproliferative neoplasms (PV, ET, myelofibrosis), Polycythaemia vera (PV), Essential thrombocythaemia (ET), Waldenström macroglobulinaemia, Hairy cell leukaemia, Peripheral T-cell lymphomas (including cutaneous T-cell lymphoma), Blastic plasmacytoid dendritic cell neoplasm (BPDCN), Burkitt lymphoma, HIV-associated (AIDS-related) lymphomas, Chronic myelomonocytic leukaemia and MDS/MPN overlap neoplasms, Systemic mastocytosis, Erdheim-Chester disease, Rosai-Dorfman disease and other histiocytic neoplasms, Langerhans cell histiocytosis (LCH), Post-transplant lymphoproliferative disorder (PTLD), FLT3-mutated acute myeloid leukaemia, IDH1- and IDH2-mutated acute myeloid leukaemia, NPM1-mutated and KMT2A-rearranged acute myeloid leukaemia, Secondary and therapy-related acute myeloid leukaemia, Acute promyelocytic leukaemia, Acute myeloid leukaemia in older or unfit patients, Smouldering multiple myeloma, Newly diagnosed multiple myeloma, transplant-eligible, Newly diagnosed multiple myeloma, transplant-ineligible, Relapsed or refractory multiple myeloma, Plasma cell leukaemia, Lower-risk myelodysplastic syndromes, Higher-risk myelodysplastic syndromes, Chronic lymphocytic leukaemia, first treatment, Richter transformation of chronic lymphocytic leukaemia, Chronic myeloid leukaemia, chronic phase, Chronic myeloid leukaemia, accelerated and blast phase, Primary myelofibrosis
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.
Cases by country
No country-level case numbers. This cancer is not mapped to a GLOBOCAN site.
One section per setting: the options named, what each is for, the trials behind them, the recorded trade-offs and the questions to ask.
Venetoclax plus rituximab for two years (MURANO) or venetoclax-obinutuzumab; pirtobrutinib after covalent BTK inhibitor failure (BRUIN CLL-321).
Acalabrutinib or zanubrutinib (ALPINE) continuously, or ibrutinib; venetoclax retreatment if the prior remission lasted a year or more.
Pirtobrutinib; lisocabtagene maraleucel CAR-T (TRANSCEND CLL 004); idelalisib-rituximab; clinical trials of BTK degraders, sonrotoclax and bispecifics; allogeneic transplant in fit young patients.
Subtypes & biomarkers
top- 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
- 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
How often this target appears
- 2014RESONATE: ibrutinib beats ofatumumab in relapsed CLL; idelalisib approved
- 2016Venetoclax approved for relapsed del(17p) CLL
- 2018MURANO: two years of venetoclax-rituximab beats chemoimmunotherapy
- 2022ALPINE: zanubrutinib beats ibrutinib head to head
- 2023Pirtobrutinib approved after BTK and BCL-2 inhibitor failure
- 2024BRUIN CLL-321 reads out; lisocabtagene maraleucel approved for double-refractory CLL
Dated changes read from the records linked to this cancer: approvals, regulatory steps, reported trials, guideline versions and milestones. Newest first; no date is inferred.
All 16 changes by month →- 2026-09-17This recordRelapsed or refractory chronic lymphocytic leukaemiaFacts on this page last checked
When this page itself was last checked or edited.
- 2025ApprovalPirtobrutinibPirtobrutinib approved in US
Relapsed/refractory CLL/SLL after a covalent BTK inhibitor (traditional approval, BRUIN CLL-321)
- 2024ApprovalLisocabtagene maraleucelLisocabtagene maraleucel approved in US
Relapsed/refractory CLL/SLL after BTK inhibitor and BCL-2 inhibitor (accelerated)
- 2024Trial resultBRUIN CLL-321BRUIN CLL-321 reported
PFS 11.
- 2024MilestoneBRUIN CLL-321BRUIN CLL-321 reads out; lisocabtagene maraleucel approved for double-refractory CLL
A milestone in how this cancer is treated.
- 2023Trial resultTRANSCEND CLL 004TRANSCEND CLL 004 reported
CR/CRi 18-20%; ORR 47%; uMRD blood 64%.
What is in development for Relapsed or refractory chronic lymphocytic leukaemia, drawn from the whole corpus: 7 items. Drugs are grouped by the most advanced trial phase they have reached anywhere; approved treatments sit under standard of care. Technologies are the methods being tested for this cancer, trials are the studies recorded here, and ideas are proposals not yet in a trial.
Drugs in phase 3 · 1
Trials under way · 2
- BELLWAVE-011 · phase 3 · Merck
- CaDAnCe-304 · phase 3 · BeOne (BeiGene)
Trials reported · 4
- ALPINE · phase 3 · 2022 · positive
- BRUIN CLL-321 · phase 3 · 2024 · positive
- RESONATE · phase 3 · 2014 · positive
- TRANSCEND CLL 004 · phase 1/2 · 2023 · positive
Open problems and what is being done
Double-refractory disease after BTK inhibitor and venetoclax has no durable option.
and how the field plans to fix it →What is being done about thisResistance to treatmentAvailable now- PirtobrutinibApproved
In trials- BRUIN CLL-321Positive
- CaDAnCe-304Recruiting
- NemtabrutinibPhase 3
Ideas and roadmapsNothing recorded yet.
Background: Drug resistance (primary and acquired). Also on OnCo: Resistance atlas · Lines of therapy.
Whether venetoclax retreatment works as well the second time, and after how long an interval.
Distinguishing CLL progression from Richter transformation early enough.
Trials
topTrials recruiting now
Country and place are remembered in this browser only. A postcode is sent to OpenStreetMap's Nominatim service to find coordinates when you press the button; nothing else leaves your device.
Landmark trials
Expert centres
topExpert centres
Columbus, OH · cancer center | United States | 1 | not matched | - | - | ||
Melbourne · research institute | Australia | none recorded | 0 | 298 | 3,639 | - | |
Indianapolis, IN · cancer center | United States | 0 | 159 | 4,238 | - | ||
Hamilton, ON · cancer center | Canada | none recorded | 0 | 103 | 1,158 | - | |
Baltimore, MD · cancer center | United States | 0 | 101 | 2,306 | - | ||
Omaha, NE · cancer center | United States | 0 | 37 | 4,159 | - | ||
Rotterdam · consortium | Netherlands | none recorded | 0 | 8 | 207 | - | |
Minneapolis, MN · cancer center | United States | 0 | not matched | - | - |
These are the things we can measure; they are not a ranking of quality. Each column is a field on the institution record or a count over what OnCo has linked; a centre that treats many patients with Relapsed or refractory chronic lymphocytic leukaemia but is thinly recorded here will look small.
Not known: OnCo holds no case-volume or outcome figures for centres, so none are shown. Where a national audit or registry publishes them, the centre's page links to it. Default order: Newsweek rank, then trials for this cancer, then research output.
Questions to ask
topQuestions to ask your oncologist about Relapsed or refractory chronic lymphocytic leukaemia
Newly diagnosed
- What is my exact diagnosis, stage, and grade, and which tests established them?Why: Everything else follows from an accurate stage and subtype.
- Which biomarkers have been tested on my tumour (for example BTK C481S and PLCG2 resistance mutations, BCL2 G101V mutation, deland TP53 mutation re-tested at relapse, Complex karyotype, IGHV status), and what were the results?Why: These results decide eligibility for targeted therapy, immunotherapy, and trials.
- Which subtype is my cancer, and does that change the recommended treatment?Why: Recognised subtypes for this cancer include Relapse after chemoimmunotherapy, Relapse after fixed-duration venetoclax, Progression on a covalent BTK inhibitor.
- Is germline (inherited) genetic testing recommended for me or my family?Why: Inherited variants can change treatment and matter for relatives.
Relapse after a BTK inhibitor
- For my situation (relapse after a btk inhibitor), which of the standard options do you recommend and why?Why: Guideline options include: Venetoclax plus rituximab for two years (MURANO) or venetoclax-obinutuzumab; pirtobrutinib after covalent BTK inhibitor failure (BRUIN CLL-321).
- Am I a candidate for Venetoclax, Rituximab, Obinutuzumab or related drugs, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
- How do the results of BRUIN CLL-321 apply to someone like me?Why: Trial populations differ from individual patients; ask how closely you match.
Relapse after venetoclax
- For my situation (relapse after venetoclax), which of the standard options do you recommend and why?Why: Guideline options include: Acalabrutinib or zanubrutinib (ALPINE) continuously, or ibrutinib; venetoclax retreatment if the prior remission lasted a year or more.
- Am I a candidate for Acalabrutinib, Zanubrutinib, Ibrutinib or related drugs, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
- How do the results of ALPINE and RESONATE apply to someone like me?Why: Trial populations differ from individual patients; ask how closely you match.
Double-refractory after BTK inhibitor and venetoclax
- For my situation (double-refractory after btk inhibitor and venetoclax), which of the standard options do you recommend and why?Why: Guideline options include: Pirtobrutinib; lisocabtagene maraleucel CAR-T (TRANSCEND CLL 004); idelalisib-rituximab; clinical trials of BTK degraders, sonrotoclax and bispecifics; allogeneic transplant in fit young patients.
- Am I a candidate for Pirtobrutinib, Lisocabtagene maraleucel, Idelalisib or related drugs, and what side effects should I expect?Why: Knowing the expected toxicities helps you plan work, family, and supportive care.
- How do the results of TRANSCEND CLL 004 apply to someone like me?Why: Trial populations differ from individual patients; ask how closely you match.
Any stage
- Are there clinical trials I could join, for example of Pirtobrutinib, Sonrotoclax, Nemtabrutinib, Lisocabtagene maraleucel?Why: Trials are how the next standard of care is set; asking early keeps options open.
- Would a second opinion at a high-volume centre change anything, and can you help arrange it?Why: Rare or high-stakes decisions benefit from a centre that treats many similar patients.
- What supportive care (symptom control, nutrition, exercise, mental health, financial help) is available from the start?Why: Supportive care improves quality of life and helps patients complete treatment.
- I read that “Double-refractory disease after BTK inhibitor and venetoclax has no durable option”. How does that affect my plan?Why: Open problems are where trials and second opinions matter most.
- I read that “Whether venetoclax retreatment works as well the second time, and after how long an interval”. How does that affect my plan?Why: Open problems are where trials and second opinions matter most.
Newly diagnosed? Read the first 60 days with Relapsed or refractory chronic lymphocytic leukaemia, then print the one-page appointment sheet with room for the answers.
Print this page for your appointment (your browser's print command). These prompts are for discussion; your clinical team knows your case.
Direct links plus the targets, companies, and technologies of this cancer's products.
technologies
6targets
5drugs
11companies
13pathways
2terms
4trials
6key papers
1Latest papers
topQuery for this cancer: (TITLE:"Relapsed or refractory chronic lymphocytic leukaemia" OR ABSTRACT:"Relapsed or refractory chronic lymphocytic leukaemia" OR TITLE:"Relapsed CLL" OR ABSTRACT:"Relapsed CLL" OR TITLE:"Refractory CLL" OR ABSTRACT:"Refractory CLL" OR TITLE:"Double-refractory CLL after BTK and BCL-2 inhibitors" OR ABSTRACT:"Double-refractory CLL after BTK and BCL-2 inhibitors" OR TITLE:"CLL after BTK inhibitor failure" OR ABSTRACT:"CLL after BTK inhibitor failure") AND (treatment OR therapy OR trial OR survival OR diagnosis). Results are unfiltered search hits about Relapsed or refractory chronic lymphocytic leukaemia, not a curated reading list.
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