What changed: Chronic lymphocytic leukaemia

When this page itself was last checked or edited.

Fixed-duration acalabrutinib + venetoclax, previously untreated CLL/SLL without del(17p)/TP53 (AMPLIFY)

Pirtobrutinib if BTK-naive-to-noncovalent; lisocabtagene maraleucel CAR-T (TRANSCEND CLL 004; accelerated approval 2024); allogeneic transplant in fit patients; PI3K inhibitors (idelalisib, duvelisib) rarely; clinical trials of degraders, sonrotoclax, bispecifics. (NCCN Category 2A)

Watch and wait with periodic counts and examination; early treatment with ibrutinib (CLL12) delayed progression but did not improve survival and is not recommended. Vaccinations and infection prevention. (NCCN Category 1 (observation))

FCR only for young, fit, IGHV-mutated, TP53-intact patients who decline targeted therapy or lack access; BR in older patients likewise. Outperformed by targeted therapy in CLL13, ELEVATE-TN, SEQUOIA, AMPLIFY. (NCCN Category 2A (select patients))

Acalabrutinib (± obinutuzumab, ELEVATE-TN) or zanubrutinib (SEQUOIA) until progression; ibrutinib where alternatives are unavailable. Preferred for del(17p)/TP53 and for patients who cannot manage venetoclax ramp-up or TLS monitoring. (NCCN Category 1 (acalabrutinib, zanubrutinib preferred))

Continuous second-generation BTK inhibitor (zanubrutinib: 5-year PFS 72%; acalabrutinib) or venetoclax-obinutuzumab; never chemoimmunotherapy; consider clinical trial and early referral for transplant/CAR-T planning if young. (NCCN Category 1)

Venetoclax + obinutuzumab for 12 months (CLL14, CLL13), or acalabrutinib + venetoclax for 14 cycles (AMPLIFY; approved February 2026), or ibrutinib + venetoclax 15 months (EU; GLOW, CAPTIVATE). uMRD at end of treatment predicts durable remission; retreatment is effective. (NCCN Category 1 (venetoclax-obinutuzumab); Category 1 (acalabrutinib-venetoclax), ESMO-MCBS 4 (CLL14))

Venetoclax-based therapy (venetoclax-rituximab 24 months, MURANO) or pirtobrutinib (BRUIN CLL-321; traditional approval December 2025); BTK degraders (BGB-16673 vs pirtobrutinib, CaDAnCe-304) in trials. (NCCN Category 1 (venetoclax-rituximab); Category 2A (pirtobrutinib))

Retreat with venetoclax-based therapy if remission lasted >2-3 years, or switch to a BTK inhibitor (acalabrutinib, zanubrutinib); pirtobrutinib if prior covalent BTKi as well. (NCCN Category 2A)

Biopsy to confirm and assess clonal relationship; chemoimmunotherapy (R-CHOP) has poor results; checkpoint inhibitor + BTK inhibitor (zanubrutinib-tislelizumab, RT1), pirtobrutinib, venetoclax-based regimens, CD20×CD3 bispecifics (epcoritamab, glofitamab), CAR-T; allogeneic transplant for responders. (NCCN Category 2A (clinical trial preferred))

Infection prophylaxis and vaccination (non-live; reduced vaccine responses), IVIG for recurrent infections with hypogammaglobulinaemia, HBV screening before anti-CD20, skin cancer surveillance (second cancers), cardio-oncology review before ibrutinib, TLS prophylaxis with venetoclax. (NCCN Category 2A)

A milestone in how this cancer is treated.

Acalabrutinib-venetoclax approved 19 February; sonrotoclax accelerated approval 13 May; CaDAnCe-304 and CELESTIAL-TNCLL enrolling.

Relapsed/refractory CLL/SLL after a covalent BTK inhibitor (traditional approval, BRUIN CLL-321)

Relapsed/refractory MCL and CLL/SLL after BTK inhibitor

BRUIN CLL-321 confirms benefit after covalent BTKi (3 December); next-generation BCL-2 inhibitor reaches patients.

First CAR-T in CLL (TRANSCEND CLL 004), accelerated

Relapsed/refractory CLL/SLL after BTK inhibitor and BCL-2 inhibitor (accelerated)

3-year PFS 76.

PFS 11.

Liso-cel accelerated approval (March); AMPLIFY fixed-duration acalabrutinib-venetoclax at ASH.

CLL/SLL accelerated approval

CLL/SLL

Relapsed MCL after BTK inhibitor (accelerated, January); CLL/SLL after BTK and BCL-2 inhibitors (accelerated, December)

CLL/SLL, all lines (SEQUOIA, ALPINE)

5-year PFS 81.

CR/CRi 18-20%; ORR 47%; uMRD blood 64%.

First BTKi to beat ibrutinib head to head; first non-covalent BTKi in CLL (December).

Fixed-duration ibrutinib + venetoclax, first-line CLL (GLOW, CAPTIVATE)

PFS HR 0.

PFS HR 0.

Venetoclax combinations beat chemoimmunotherapy in fit patients; ibrutinib-venetoclax approved in Europe.

CLL after ≥2 therapies; FL after ≥2 therapies

CR 55%; uMRD 77%; 4-year PFS ~79%.

PFS HR 0.

MRD in chronic lymphocytic leukaemia

Relapsed or refractory CLL/SLL; relapsed or refractory mantle cell lymphoma

CLL/SLL

First-line CLL with obinutuzumab (CLL14)

CLL/SLL, first-line and relapsed (ELEVATE-TN, ASCEND)

Previously untreated CLL with venetoclax, fixed duration (CLL14); with acalabrutinib (ELEVATE-TN)

6-year PFS 53.

6-year median PFS not reached vs 27.

Venetoclax-obinutuzumab for 12 months; ELEVATE-TN and ASCEND establish acalabrutinib.

CLL/SLL with rituximab (MURANO)

Relapsed/refractory CLL/SLL after ≥2 prior therapies; FL (withdrawn 2021)

CLL with 17p deletion after ≥1 therapy: first BCL-2 inhibitor

First-line CLL

First-line CLL (RESONATE-2)

CLL with 17p deletion

A milestone in how this cancer is treated.

First BCL-2 inhibitor; RESONATE-2 moves ibrutinib to untreated CLL.

Relapsed CLL

Relapsed mantle cell lymphoma; CLL after one prior therapy or with del(17p)/TP53 mutation

Relapsed CLL (RESONATE); del(17p) CLL

CLL, FL

Relapsed CLL with rituximab; relapsed FL and SLL (accelerated, withdrawn 2022)

Previously untreated CLL with chlorambucil; later extended treatment and relapsed CLL with fludarabine and cyclophosphamide

PFS HR 0.

A milestone in how this cancer is treated.

PFS HR 0.22 vs ofatumumab; the BTK era begins. Idelalisib approved the same year.

Previously untreated CLL with chlorambucil (CLL11)

CLL11 (obinutuzumab-chlorambucil) and ibrutinib's first approval (MCL).

CLL, indolent NHL, multiple myeloma (national approvals)

CLL refractory to fludarabine and alemtuzumab (conditional; authorisation since withdrawn)

CLL with fludarabine and cyclophosphamide

CLL8 shows fludarabine-cyclophosphamide-rituximab beats FC on OS; rituximab approved in CLL.

CLL refractory to fludarabine and alemtuzumab (accelerated)

CLL; indolent B-cell NHL progressed within 6 months of rituximab

B-CLL after fludarabine (MabCampath; authorisation withdrawn 2012)

B-cell chronic lymphocytic leukaemia (single agent)

del(17p) and del(11q) adverse; del(13q) favourable.

Hamblin and Damle show unmutated IGHV means aggressive disease.

B-cell chronic lymphocytic leukaemia after at least one alkylating-agent regimen

Clinical staging by lymphocytosis, nodes, organomegaly, cytopenias; Binet system follows in 1981.

Chronic lymphocytic leukaemia, lymphomas and essential thrombocythaemia (historic label)

Chronic lymphocytic leukaemia; Hodgkin and non-Hodgkin lymphomas (palliative)