Seminar

www.thelancet.com Published online July 25, 2024 https://doi.org/10.1016/S0140-6736(24)00595-6 1

Chronic lymphocytic leukaemia

Nitin Jain, William G Wierda, Susan O’Brien

The last decade has seen remarkable progress in our understanding of disease biology of chronic lymphocytic

leukaemia (CLL) and the development of novel targeted therapies. Randomised clinical trials have reported improved

progression-free survival and overall survival with targeted therapies compared with chemoimmunotherapy, and

thereby the role of chemoimmunotherapy in todays’ era for treatment of CLL is limited. Bruton tyrosine kinase (BTK)

inhibitors, BCL2 inhibitors, and CD20 monoclonal antibodies have been established as appropriate therapy options

for patients with CLL, both as the first-line treatment and in the treatment of relapsed or refractory CLL. Several

ongoing phase 3 trials are exploring different combinations of targeted therapies, and the results of these trials might

change the treatment framework in first-line treatment of CLL. Non-covalent BTK inhibitors, chimeric antigen

receptor T-cell therapy, and other therapeutic strategies are being investigated in relapsed CLL. Some of the therapies

used in relapsed CLL, such as non-covalent BTK inhibitors, are now being pursued in earlier lines of therapy,

including first-line treatment of CLL.

Introduction

Chronic lymphocytic leukaemia (CLL) is a haematological

malignancy of B cells characterised by clonal proliferation

of CD5+

B cells. In the USA, CLL is the most common

leukaemia and, in 2024, approximately 20700 patients are

expected to be diagnosed with CLL and approximately

4440 deaths from CLL are expected.1

In 2019, the estimated

incidence of CLL was approximately 100000 new cases

and approximately 44000 deaths worldwide.2

CLL mainly

affects older adults, with the median age at diagnosis older

than 70 years. The estimated incidence of new cases of

CLL worldwide in 2019 was 1·34 per 100000 people, with a

male to female ratio of 1·14.2

The incidence of CLL is

about five to ten times lower in Asian countries compared

with the USA or Europe.2–5 The risk of CLL is not increased

among people from Asian countries who have settled in

Western countries such as the USA and Europe, indicating

the major role of genetic factors in CLL predisposition,

rather than environmental factors.5,6

Diagnosis and differential diagnosis

The diagnosis of CLL requires at least 5×10⁹/L monoclonal

B lymphocytes in the peripheral blood.7–9 CLL cells coexpress CD5 along with B-cell antigen CD19. CLL cells also

express CD23, CD200, and CD43. Expression of surface

IgM or IgD and CD20 on B cells in CLL is characteristically

lower than normal B-cell expression. CD10 is not expressed

on CLL cells. FMC7 and CD79b are usually negative or

weakly expressed. For most patients, diagnosis of CLL can

be established by flow cytometry on peripheral blood,

without the need for bone marrow or lymph node biopsy.

About 5–10% of patients with CLL present with

predominately lymph node-based disease, which is

characterised as small lymphocytic lymphoma when

clonal B lymphocytes in the peripheral blood are less

than 5×10⁹/L without any cytopenia (figure 1). Patients

diagnosed with small lymphocytic lymphoma can

maintain the diagnosis at the time of disease progression

or develop to the CLL phase of the disease over time.

Patients with clonal B cells with an immunophenotype

consistent with CLL, a clonal B-cell count of less than

5×10⁹/L, and without any cytopenia, lymphadenopathy,

or organomegaly are categorised as having monoclonal

B-cell lymphocytosis. Monoclonal B-cell lymphocytosis is

seen in up to 5–12% of the general population, and in up

to 22% among relatives of patients with CLL.10

Monoclonal B-cell lymphocytosis is associated with

increased risk of progression to CLL, increased risk of

infections, and increased risk of secondary malignancies.11

Bone marrow involvement with clonal B cells is seen in

patients with CLL, small lymphocytic lymphoma, and

monoclonal B-cell lymphocytosis and, therefore, cannot

be used to differentiate between these disease entities.

Distinguishing CLL from mantle cell lymphoma is

important as CD5 is expressed in both diseases. However,

in contrast to CLL, mantle cell lymphoma cells are

typically positive for FMC7; negative for CD23 and

CD200; have higher CD20 expression; and have strong

surface IgM or IgD. Additionally, the presence of the

t(11;14) translocation, positive nuclear cyclin D1 staining,

or both, is indicative of mantle cell lymphoma.

Genomics

Several clinically relevant genomic alterations were

identified in patients with CLL and many of them (eg,

IGHV gene mutation status, CLL fluorescence in situ

hybridisation [FISH] abnormalities, and assessment of

TP53 mutation) constitute clinically important tests

Published Online

July 25, 2024

https://doi.org/10.1016/

S0140-6736(24)00595-6

Department of Leukemia,

The University of Texas MD

Anderson Cancer Center,

Houston, TX, USA

(Prof N Jain MD,

Prof W G Wierda MD PhD);

Division of Hematology/

Oncology, Department of

Medicine, Chao Family

Comprehensive Cancer Center,

University of California Irvine

Medical Center, Orange, CA,

USA (Prof S O’Brien MD)

Correspondence to:

Professor Susan O’Brien,

Division of Hematology/

Oncology, Department of

Medicine, Chao Family

Comprehensive Cancer Center,

University of California Irvine

Medical Center,

Orange, CA 92868, USA

obrien@hs.uci.edu

Search strategy and selection criteria

We searched for relevant English language manuscripts in

PubMed from Jan 1, 2000 to March 1, 2023. We used the

search terms “chronic lymphocytic leukemia” or “CLL” in

combination with the terms “diagnosis”, “targeted therapy”,

“chemotherapy”, “immunotherapy”, “MRD”, “measurable

residual disease”, “minimal residual disease”, “prognosis”,

“outcomes”, or “complications”. Relevant articles and

abstracts were critically reviewed. We searched reference lists

of the articles for other pertinent and important articles.

Priority was given to manuscripts published in the past

5 years and randomised controlled trials.

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2 www.thelancet.com Published online July 25, 2024 https://doi.org/10.1016/S0140-6736(24)00595-6

before starting therapy for CLL.12 IGHV gene

mutation assessment categorises patients as having

IGHV-unmutated CLL (≥98% identity with germline)

versus IGHV-mutated CLL (<98% identity with

germline). IGHV-mutated clones tend to grow at a

slower pace than IGHV-unmutated clones and have

improved outcomes compared with IGHV-unmutated

CLL with the use of chemoimmunotherapy. Long-term

outcomes with continuous Bruton tyrosine kinase (BTK)

inhibitor treatment appear similar for IGHV-mutated

versus IGHV-unmutated CLL; however, patients with

IGHV-mutated CLL treated with time-limited

venetoclax–CD20 monoclonal antibody therapy appear

to have better long-term outcomes compared with those

with IGHV-unmutated CLL. CLL FISH testing

categorises patients into del(17p), del(11q), trisomy 12,

del(13q), and normal FISH. With chemoimmunotherapy,

patients with del(17p) had the worst outcomes, and those

with isolated del(13q) had the best outcomes.

However, with novel targeted therapies, only del(17p)

correlates with inferior outcomes compared with other

FISH subgroups. TP53 mutation can either co-occur

with del(17p) or occur in the absence of del(17p). Most,

but not all, studies indicate that the presence of either

del(17p) or TP53 mutation have similar negative effects

on clinical outcomes.13–15 There are conflicting data on

whether biallelic loss of function of TP53—having both

del(17p) and a TP53 mutation, or two different TP53

mutations—might be more adverse than a single

aberration.

Clinical features

Most people are diagnosed with CLL incidentally when

noted to have an elevated white blood cell count or elevated

lymphocyte count on a routine blood test, and less

commonly after identification of enlarged lymph nodes. In

the early stages of the disease, most patients are

asymptomatic. Over time, with disease progression,

patients can develop B symptoms (eg, fever, night sweats,

and weight loss) and worsening fatigue.16 Progressive

lymphadenopathy or organomegaly can lead to discomfort.

Worsening anaemia and thrombocytopenia can lead to

dyspnoea on exertion and bleeding complications,

although major bleeding is rare. Some patients with CLL

present with or develop progressive hypogammaglobulinaemia. Most patients with hypogammaglobinaemia

do not require any specific intervention. Patients with

hypogammaglobinaemia can develop frequent infections,

especially upper respiratory tract infections and

pneumonia. We recommend immunoglobulin supplementation for patients with hypogammaglobulinaemia

(typically IgG <500 mg/dL) and severe infections, such as

those requiring hospitalisation or repetitive infections

impairing quality of life.

Patients with CLL can also develop autoimmune

complications, most commonly autoimmune haemolytic

anaemia and immune thrombocytopenia.17 Vigilant, ageappropriate cancer screening is recommended for all

patients with CLL.18

Treatment

Most patients diagnosed with CLL do not need treatment

at diagnosis and are placed on active observation (a

watch-and-wait approach). During active observation,

most patients undergo serial monitoring with collection

of medical history, physical examination, and complete

blood count assessment every 3–6 months. Indications

for initiation of CLL therapy were established by the

International Workshop on Chronic Lymphocytic

Leukemia (iwCLL), and the most common indications

include progressive marrow failure (haemoglobin

<10 mg/dL and platelet count <100×10⁹/L) due to CLL

infiltration of the bone marrow; massive (≥10 cm in

longest dimension) or progressive or symptomatic

lymphadenopathy; massive (≥6 cm below left costal

margin) or progressive or symptomatic splenomegaly;

clinically significant symptoms attributable to

CLL affecting quality of life; symptomatic extranodal

involvement; and autoimmune anaemia or thrombocytopenia poorly responsive to steroids.

The iwCLL guidelines also indicate progressive

lymphocytosis (≥50% increase over 2 months or

lymphocyte doubling time <6 months) as an indication for

treatment. In our opinion, this criterion of progressive

lymphocytosis alone should not be used to initiate

treatment for CLL unless accompanied by other treatment

initiation criteria. Additionally, white blood cell count can

increase transiently after intercurrent illness or with use of

steroids and this should be factored into decision making.

In patients who present with substantially elevated

absolute lymphocyte count (eg, >400×10⁹/L) and without

Figure 1: Chronic lymphocytic leukaemia versus small lymphocytic lymphoma versus monoclonal B-cell

lymphocytosis

• Without lymphadenopathy

• Without organomegaly

• Without symptoms

Monoclonal B-cell

lymphocytosis

• Low-count monoclonal B-cell

lymphocytosis

(<0·5 K/µL clonal B cells)

• High-count monoclonal B-cell

lymphocytosis

(≥0·5–4·99 K/µL clonal B cells)

<5 K/µL clonal B cells, but no

cytopenias

• Clonal B cells

• CD5+

, CD19+

, and CD23+

≥5 K/µL clonal B cells or

cytopenias

Chronic lymphocytic leukaemia

• Lymphadenopathy

• With or without organomegaly

• With or without symptoms

Small lymphocytic lymphoma

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www.thelancet.com Published online July 25, 2024 https://doi.org/10.1016/S0140-6736(24)00595-6 3

any other indications for treatment, we recommend close

monitoring with low threshold for treatment initiation;

this recommendation is appropriate in our view for clinical

management as substantially elevated lymphocyte count

can make treatment initiation with targeted therapies

more challenging (eg, more toxicities and need for hospital

admission). For patients with anaemia, it is important to

rule out other causes of anaemia besides CLL, such as iron

deficiency anaemia, autoimmune haemolytic anaemia, or

myelodysplastic syndrome. Some patients, especially those

with IGHV-mutated CLL, can present with a slowly

declining platelet count, and the platelet count can remain

stable over time in the range of 70–100×10⁹/L without any

other indication for therapy; these patients can be managed

with continued observation.

The Rai and Binet staging systems were developed for

clinical staging of CLL.19,20 Both systems rely on common

laboratory parameters and physical examination, and do

not require imaging. More recently, the CLL International

Prognostic Index (CLL-IPI) was established using

patient-level data from approximately 3400 patients.21

Five factors were independently associated with worse

survival; namely, the presence of del(17p) or mutated

TP53; IGHV-unmutated CLL; β2-microglobulin level

greater than 3·5 mg/L; clinical stage (Rai I–IV or

Binet B–C); and age older than 65 years. Notably, these

staging systems were derived from patient data from the

chemoimmunotherapy era. The utility of these staging

systems in the era of novel targeted therapies remains to

be determined and, overall, these staging systems have

limited use in routine clinical practice.

Early initiation of therapy with either chemoimmunotherapy 22–24 or, more recently, with ibrutinib25 in

patients who do not meet iwCLL treatment criteria was

not shown to be beneficial. Ongoing trials, such as

SWOG S1925, are exploring venetoclax-based therapy for

early intervention in patients at high risk for disease

progression with the primary endpoint of overall

survival.26 The current recommendation remains to

continue observation for people who do not meet iwCLL

treatment criteria, even if they are at a higher risk for

early disease progression. Notably, patients with del(17p)

or TP53-mutated CLL with mutated IGHV can have long

time to first treatment.27 Several predicting models, such

as CLL1-PM,28 CLL-IPI,21,29 and IPS-E,30 have been

developed to estimate time to first treatment.

First-line therapy

Until the last few years, chemoimmunotherapy was

considered the standard first-line therapy for patients with

CLL. Chemoimmunotherapy treatment evolved from the

use of alkylating agents several decades ago, to the

introduction of purine analogues, to CD20 monoclonal

antibody treatment in the 1990s, and then to combination

chemoimmunotherapy regimens (eg, fludarabine,

cyclophosphamide, and rituximab; bendamustine and

rituximab; and chlorambucil and obinutuzumab). For

younger patients (generally younger than 65 years) without

clinically significant comorbidities, fludarabine, cyclophosphamide, and rituximab was previously recommended as

standard therapy. Older adults (generally 65 years or older)

were treated with bendamustine and rituximab or with

combined chlorambucil and obinutuzumab.

However, with the introduction of targeted therapies,

such as ibrutinib, about a decade ago,31,32 chemoimmunotherapy was superseded by targeted therapies, with several

randomised studies in first-line CLL reporting improved

progression-free survival15,33–48 and improved overall

survival33,34,39,40,47,48 with targeted therapies compared with

chemoimmunotherapy. Similarly, randomised studies in

patients with relapsed or refractory CLL showed improved

progression-free survival49–56 and improved overall

survival49–52,55,56 with targeted therapies compared with

chemoimmunotherapy. Consequently, chemoimmunotherapy is now rarely used for patients with CLL.

For first-line treatment, several classes of targeted

agents are approved including covalent BTK inhibitors,

such as ibrutinib, acalabrutinib, and zanubrutinib, which

form covalent bonds with the cysteine 481 residue of the

BTK protein; BCL2 inhibitors, such as venetoclax; and

CD20 monoclonal antibodies, such as rituximab and

obinutuzumab. Figure 2 shows approved targeted

therapies for patients with CLL and their corresponding

mechanisms of action.

Ibrutinib was the first covalent BTK inhibitor approved

for patients with CLL by the US Food and Drug

Figure 2: Approved targeted therapies for patients with CLL and corresponding mechanism of action

CAR T=chimeric antigen receptor T cell. CLL=chronic lymphocytic leukaemia. mAb=monoclonal antibody.

Anti-CD20 mAb

BCL2 antagonist BCL2

SYK

BTK

PI3K

PLCG2

LYN

B-cell receptor

BTK inhibitors

PI3K inhibitors

CD19

CD79 A

CD79 B

BLNK

AKT

BCL2 BIM

BAX

BIM

BAX

Cyto C

CD20

• Venetoclax

• Lisocabtagene maraleucel

PKC

ERK NF-κB

Transcriptional

regulation

• Idelalisib

• Duvelisib

• Ibrutinib

• Acalabrutiniub

• Zanubrutinib

• Pirtobrutinib

• Rituximab

• Obinutuzumab

CD19 CAR T

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4 www.thelancet.com Published online July 25, 2024 https://doi.org/10.1016/S0140-6736(24)00595-6

Administration, initially for relapsed or refractory CLL in

February, 2014, and for first-line treatment of CLL in

March, 2016. With ibrutinib therapy, the majority of

patients had partial remission; complete remission is

less common, and reaching undetectable measurable

residual disease (U-MRD) is rare. Most patients receiving

a BTK inhibitor, such as ibrutinib, will have an increase

in absolute lymphocyte count—sometimes several fold

from pretreatment lymphocyte count—soon after

initiation of treatment, due to redistribution of CLL cells

from lymph nodes and other sites to the peripheral blood

(redistribution lymphocytosis). This rise in lymphocyte

count is not detrimental to the overall response to

therapy, and resolves over time with continued BTK

inhibitor therapy in most patients, without any additional

intervention. Common adverse effects with ibrutinib

include arthralgias or myalgias, easy bruising, diarrhoea,

skin and nail changes, atrial fibrillation, bleeding, and

hypertension.

In the RESONATE-2 trial, previously untreated patients

with CLL aged 65 years and older who met iwCLL

treatment indications were randomly assigned to receive

continuous ibrutinib (n=136; median age 73 years) or

12 cycles of chlorambucil (n=133; median age 72 years).33,34

After a median follow-up of 7·4 years in the ibrutinib

group, of 136 participants, 57 (42%) were still taking

ibrutinib, 32 (24%) discontinued ibrutinib due to adverse

events, and 18 (13%) discontinued ibrutinib due to disease

progression. As a best response, 34% of participants had

complete remission or complete remission with

incomplete count recovery and 59% had partial remission

or partial remission with lymphocytosis. The estimated

7-year progression-free survival was 59% for patients

treated with ibrutinib, independent of IGHV gene

mutation status.

The RESONATE-2 trial did not have a CD20 monoclonal

antibody in either group; the iLLUMINATE trial was

designed for older adults with CLL, whereby patients

were randomly assigned to receive either continuous

ibrutinib plus six cycles of obinutuzumab (n=113; median

age 70 years) or six cycles of both chlorambucil plus

obinutuzumab (n=116; median age 72 years).35,36 The

estimated 3·5-year progression-free survival was 74% in

the ibrutinib plus obinutuzumab group, compared with

33% in the chlorambucil plus obinutuzumab group.

Unlike ibrutinib monotherapy, where U-MRD remission

is rare, 33% and 25% of the patients treated with ibrutinib

plus obinutuzumab in the iLLUMINATE trial had

U-MRD (sensitivity 0·01%) remission in peripheral blood

and bone marrow, respectively.36 Despite the improved

U-MRD, the progression-free survival of patients in the

ibrutinib plus obinutuzumab group in the iLLUMINATE

trial was similar to the ibrutinib group in the RESONATE-2

trial, with the caveat that there were more patients at high

risk treated in the iLLUMINATE trial. Currently, there are

no randomised data comparing ibrutinib with or without

obinutuzumab, and our current practice, outside of

clinical trials, is to use ibrutinib monotherapy without the

addition of a CD20 monoclonal antibody.

In the Alliance A041202 trial, patients with CLL aged

65 years or older requiring therapy were randomly

assigned to receive bendamustine and rituximab (n=183),

ibrutinib (n=182), or ibrutinib and rituximab (n=182).37,38

Both ibrutinib groups had superior progression-free

survival compared with the bendamustine and rituximab

group; this progression-free survival benefit was

restricted to patients with IGHV-unmutated CLL, with

no difference among patients with IGHV-mutated CLL.

Addition of rituximab to ibrutinib did not improve

progression-free survival compared with ibrutinib

monotherapy.

The ECOG E1912 trial was designed for patients with

CLL aged 70 years or younger, who could tolerate

fludarabine, cyclophosphamide, and rituximab.39,40 In this

trial, patients were randomly assigned to receive six cycles

of fludarabine, cyclophosphamide, and rituximab (n=158)

or continuous ibrutinib plus six cycles of rituximab

(n=352). Patients who received ibrutinib and rituximab

had improved progression-free survival compared with

those who received fludarabine, cyclophosphamide, and

rituximab, with the benefit among patients with IGHVunmutated CLL and those with IGHV-mutated CLL.

Notably, there was superior overall survival for patients in

the ibrutinib and rituximab group compared with the

fludarabine, cyclophosphamide, and rituximab group,

with the caveat that there were few deaths in either group.

Similar to the E1912 trial, in the FLAIR trial conducted in

the UK, patients were randomly assigned to receive six

cycles of fludarabine, cyclophosphamide, and rituximab

(n=385) or continuous ibrutinib and six cycles of

rituximab (n=386).41 Unlike the E1912 trial, in the FLAIR

trial, the progression-free survival benefit for ibrutinib

and rituximab over fludarabine, cyclophosphamide, and

rituximab was only seen among patients with IGHVunmutated CLL, and there was no overall survival benefit.

Second-generation covalent BTK inhibitors, such as

acalabrutinib57 and zanubrutinib,58 were developed with

more selectivity for BTK inhibition than first generation;

fewer adverse events have been reported for these agents

than ibrutinib in head-to-head trials in relapsed or

refractory CLL.59,60 In first-line treatment of CLL,

acalabrutinib was evaluated in a phase 3 trial (ELEVATETN) comparing continuous acalabrutinib monotherapy

(n=179; median age 70 years), continuous acalabrutinib

plus six cycles of obinutuzumab (n=179; median age

70 years), and six cycles of both chlorambucil and

obinutuzumab (n=177; median age 71 years).42 73 (14%) of

535 patients had del(17p) or TP53-mutated CLL, and

337 (63%) had IGHV-unmutated CLL. At 6 years,

progression-free survival was 78% for the acalabrutinib

and obinutuzumab group, 62% for the acalabrutinib

monotherapy group, and 17% for the chlorambucil plus

obinutuzumab group.43 Both groups containing

acalabrutinib had statistically superior progression-free

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www.thelancet.com Published online July 25, 2024 https://doi.org/10.1016/S0140-6736(24)00595-6 5

survival compared with chlorambucil and obinutuzumab.

Notably, this trial reported progression-free survival

improvement with acalabrutinib plus obinutuzumab

versus acalabrutinib monotherapy (hazard ratio [HR]

0·58, 95% CI 0·39–0·86; p=0·02). Addition of

obinutuzumab adds to infusion reactions and increases

the risk of myelosuppression, and with the caveat of a

small number of patients with del(17p) or TP53 mutated

CLL, there was no benefit of adding obinutuzumab to

acalabrutinib for this high risk subgroup. In first-line

treatment of CLL, zanubrutinib was evaluated in the

phase 3 SEQUOIA trial, comparing zanubrutinib

monotherapy (n=241; median age 70 years) and

bendamustine and rituximab (n=238; median age

70 years).44 Patients with del(17p) CLL were excluded from

the randomised cohort. 28 (6%) of 455 patients had TP53-

mutated CLL and 246 (53%) of 465 patients had IGHVunmutated CLL. The 3·5-year progression-free survival

was superior for the zanubrutinib group compared with

bendamustine and rituximab (82·4% vs 50%, respectively;

p<0·001) and was significantly improved for both IGHVunmutated CLL and IGHV-mutated CLL.61

12 cycles of venetoclax plus six cycles of obinutuzumab

provides a 1-year time-limited approach for first-line

treatment of patients with CLL. This treatment was

assessed in the phase 3 CLL14 trial, in which patients with

CLL were randomly assigned to receive venetoclax plus

obinutuzumab (n=216; median age 72 years) or 12 cycles of

chlorambucil plus six cycles of obinutuzumab (n=216;

median age 71 years).15,45 49 (12%) of 417 patients had

del(17p) or TP53-mutated CLL, and 244 (60%) of

408 patients had IGHV-unmutated CLL. About 3 months

after the end of treatment, U-MRD (sensitivity 0·01%)

remission in the venetoclax and obinutuzumab group was

noted in 76% of peripheral blood samples and 57% of

bone marrow samples. At 6 years from the start of

treatment, the progression-free survival was 53·1% in the

venetoclax and obinutuzumab group, versus 21·7% in the

chlorambucil and obinutuzumab group (HR 0·35,

p<0·0001).62 Notably, for patients with IGHV-mutated

CLL in the venetoclax and obinutuzumab group, there

was improved 6-year progression-free survival of

approximately 70% compared with approximately

45% for patients with IGHV-unmutated CLL. U-MRD at

the end of 1 year of treatment predicted for longer

progression-free survival and overall survival for patients

who reached U-MRD. In the CLL13 trial, 926 patients with

previously untreated CLL were randomly assigned to

chemoimmunotherapy (fludarabine, cyclophosphamide,

and rituximab for patients ≤65 years and bendamustine

and rituximab for those >65 years), versus venetoclax plus

rituximab versus venetoclax plus obinutuzumab versus

venetoclax plus obinutuzumab plus ibrutinib.46 The

median age was 60–62 years, depending on the group to

which patients were randomly assigned. Patients with

del(17p) or TP53-mutated CLL were excluded. The two

Participants

(N)

Study groups Primary

endpoint

ClinicalTrials.gov ID

Control group Investigational group A Investigational group B

First line

ACE-CL-311 780 Fludarabine, cyclophosphamide,

and rituximab, or bendamustine

and rituximab

Acalabrutinib and venetoclax Acalabrutinib, venetoclax, and

obinutuzumab

PFS NCT03836261

ECOG-ACRIN EA9161 720 Ibrutinib and obinutuzumab Ibrutinib, obinutuzumab, and

venetoclax

·· PFS NCT03701282

Alliance A041702 454 Ibrutinib and obinutuzumab Ibrutinib, obinutuzumab, and

venetoclax

·· PFS NCT03737981

CLL17 909 Ibrutinib Venetoclax and obinutuzumab Venetoclax and ibrutinib PFS NCT04608318

MAJIC 750 Venetoclax and obinutuzumab Acalabrutinib and venetoclax ·· PFS NCT05057494

CLL16* 178 Venetoclax and obinutuzumab Acalabrutinib, venetoclax, and

obinutuzumab

·· PFS NCT05197192

CLL18 813 Venetoclax and obinutuzumab Venetoclax and pirtobrutinib

(fixed duration)

Venetoclax and pirtobrutinib

(MRD guided)

PFS ··

BRUIN CLL-313 250 Bendamustine and rituximab Pirtobrutinib ·· PFS NCT05023980

BRUIN CLL-314† 650 Ibrutinib Pirtobrutinib ·· ORR NCT05254743

BGB-11417-301 640 Venetoclax and obinutuzumab Zanubrutinib and sonrotoclax ·· PFS NCT06073821

Relapsed or refractory

BRUIN CLL-321 250 Bendamustine and rituximab or

idelalisib and rituximab

Pirtobrutinib ·· PFS NCT04666038

BRUIN CLL-322 600 Venetoclax and rituximab Venetoclax, rituximab, and

pirtobrutinib

·· PFS NCT05254743

MRD=measurable residual disease. ORR=overall response rate. PFS=progression-free survival. *At least one risk factor (del[17p], TP53 mutation, or complex karyotype [≥3 abnormalities]) must be present.

†Allows both treatment-naive and relapsed or refractory CLL; patients must be Bruton tyrosine kinase inhibitor naive.

Table 1: Selected phase 3 trials in chronic lymphocytic leukaemia

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6 www.thelancet.com Published online July 25, 2024 https://doi.org/10.1016/S0140-6736(24)00595-6

groups with venetoclax plus obinutuzumab (with or

without ibrutinib) led to higher U-MRD rates and higher

4-year progression-free survival compared with the

chemoimmunotherapy and venetoclax plus rituximab

groups.63

Throughout the last decade, a fully oral time-limited

regimen of ibrutinib and venetoclax has been increasingly

investigated, and more recently approved outside of the

USA, as a first-line therapy for patients with CLL.47,48,64-68 In

a trial from the MD Anderson Cancer Center (MDACC),

combined ibrutinib and venetoclax was given for 24 cycles

with the provision of 12 additional cycles of combined

treatment for patients with persistent bone marrow MRD

(sensitivity 0·01%).64,65 120 patients, with a median age of

64·5 years, were treated. This trial preferentially enrolled

patients with high-risk genomic profile and, consequently,

100 (86%) of 116 patients had IGHV-unmutated CLL and

27 (23%) of 120 patients had del(17p) or TP53-mutated

CLL. 86 (72%) of 120 patients had bone marrow U-MRD

(sensitivity 0·01%) as best response and 5-year progressionfree survival was 89·8%.69 Similar results were reported in

the CAPTIVATE trial in which patients with a median age

of about 60 years were either assigned to receive 12 cycles

of combined ibrutinib and venetoclax (fixed-duration

cohort) or an MRD-driven approach where additional

therapy was given after cycle 12, depending on MRD status

(MRD cohort).66,67 In both cohorts, U-MRD (sensitivity

0·01%) in peripheral blood was noted in approximately

75% of patients, and for the fixed-duration cohort, 4·5-year

progression-free survival was 70%.70 In the recently

reported UK FLAIR trial, patients were randomly assigned

to receive fludarabine, cyclophosphamide, and rituximab

(n=263) versus combined ibrutinib and venetoclax

(n=260).48 The duration of combined ibrutinib and

venetoclax was MRD directed and ranged from 2 years to

6 years. The estimated 3-year progression-free survival was

97·2% for ibrutinib and venetoclax versus 76·8% for

fludarabine, cyclophosphamide, and rituximab (HR 0·13

p<0·001). Notably, there was significant improvement

(p<0·005) in overall survival for the ibrutinib and

venetoclax group versus fludarabine, cyclophosphamide,

and rituximab. Combined ibrutinib and venetoclax was

evaluated in the GLOW trial, in which patients received

ibrutinib and venetoclax versus chlorambucil and

obinutuzumab.47 Notably, patients in the GLOW trial were

older, with a median age of 71 years, than patients in the

MDACC (median age 64·5 years) and CAPTIVATE

(median age 58–60 years) trials. The estimated 4·5-year

Participants

(N)

Median age

(range)

Disease characteristics Progression-free

survival

U-MRD rate (sensitivity 0·01%)

Peripheral blood Bone marrow

Venetoclax and obinutuzumab (CLL14 trial)15,45 216 72 years (43–89) 61% U-IGHV; 12% TP53 aberrant 63% at 5 years;

53% at 6 years

76% (3 months

after EOT, C15)

57% (3 months

after EOT, C 15)

Venetoclax and obinutuzumab (CLL13 trial)46,63 229 62 years (31–83) 59% U-IGHV; 0% TP53 aberrant 81·8% at 4 years 87% (C 15) 73% (final

restaging)

Ibrutinib and venetoclax (MDACC trial)64,65,69 120 64·5 years (26–88) 86% U-IGHV; 23% TP53 aberrant 89·8% at 5 years ND 52% (C 12);

64% (C 24); 72%

(best)

Ibrutinib and venetoclax (CAPTIVATE trial,

MRD cohort)66

164 58 years (28–69) 60% U-IGHV; 20% TP53 aberrant >95% at 2·5 years 75% (best) 68% (best)

Ibrutinib and venetoclax (CAPTIVATE trial, FD cohort)67,70 159 60 years (33–71) 57% U-IGHV; 17% TP53 aberrant 70% at 4·5 years 77% (best) 60% (best)

Ibrutinib and venetoclax (FLAIR trial)48 260 62 years (NR) 55% U-IGHV; del(17p) excluded 97·2% at 3 years 86% (best) 62% (best)

Ibrutinib and venetoclax (GLOW trial)47,71 106 71 years (47–93) 68% U-IGHV; 7% TP53-mutated;

del(17p) excluded

66·5% at 4·5 years 55% (EOT, C 18) 52% (EOT, C 18)

Zanubrutinib and venetoclax (SEQUOIA trial, arm D)76 49 65 years (25–86) 88% U-IGHV; 100% TP53 aberrant >95% at 1 year NR NR

Ibrutinib, venetoclax, and obinutuzumab (OSU trial)72,77 25 59 years (24–77) 71% U-IGHV; 12% del(17p);

TP53 mutation status NR

96% at 4 years 72% (C 16) 60% (C 16)

Ibrutinib, venetoclax, and obinutuzumab

(CLL2-GIVe trial)75

41 62 years (35–85) 78% U-IGHV; 100% TP53 aberrant 80% at 3 years 78% (C 15) 66% (C 15)

Ibrutinib, venetoclax, and obinutuzumab

(CLL13 trial)46,63

231 60 years (30–84) 55% U-IGHV; 0% TP53 aberrant 85·5% at 4 years 92% (C 15) 78%

(final restaging)

Ibrutinib, venetoclax, and obinutuzumab

(A041702 trial)78

233 74 years (65–89) 47% U-IGHV; 13% del(17p);

TP53 mutation status NR

85% at 1·5 years NR 87% (among

evaluable at

C 14)*

Acalabrutinib, venetoclax, and obinutuzumab

(DFCI trial)73,79

68 63 years (36–80) 77% U-IGHV; 60% TP53 aberrant 93% at 3 years 86% (C 16) 86% (C 16)

Zanubrutinib, venetoclax, and obinutuzumab

(BOVen trial)74,80

52 62 years (23–77) 71% U-IGHV; 17% TP53 aberrant ~85% at 3 years 96% (best) 92% (best)

C=cycle (eg, C 15=cycle 15). EOT=end of treatment. ND=not done. NR=not reported. U-IGHV=unmutated immunoglobulin heavy chain variable region. U-MRD=undetectable measurable residual disease.

*48% of all treated patients; 87% of all evaluable patients.

Table 2: Outcomes of venetoclax-based treatment regimens from selected first-line trials in chronic lymphocytic leukaemia

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progression-free survival was superior for the ibrutinib

and venetoclax group versus the chlorambucil and

obinutuzumab group (66·5% vs 19·5%, respectively;

p<0·0001).71 On the basis of this trial, combined ibrutinib

plus venetoclax was approved in the EU in 2022, and

several other countries (but not the USA).

Several trials are investigating the triplet combination

of a BTK inhibitor with venetoclax and obinutuzumab for

patients with CLL. All approved covalent BTK inhibitors

(eg, ibrutinib, acalabrutinib, and zanubrutinib) have

been combined with venetoclax and obinutuzumab in

trials with high rates of U-MRD remission.46,72–75 Several

ongoing phase 3 trials (table 1) are evaluating these

combinations in a randomised way; currently the triplet

combination remains investigational, and it remains to

be seen if triplet therapy will be superior to doublet or

monotherapy. Table 2 lists outcomes of selected

venetoclax-based combination trials in first-line

treatment of CLL.

First-line treatment of TP53-aberrant CLL

Long-term activity of ibrutinib monotherapy was reported

in 34 patients with previously untreated TP53-aberrant

CLL with a 6-year progression-free survival of 61%.81

Several additional studies reported promising long-term

efficacy of BTK inhibitors with or without CD20

monoclonal antibody therapy for patients for TP53-

aberrant CLL (table 3). In one of the largest prospective

trials in first-line TP53-aberrant CLL, 111 patients received

continuous zanubrutinib monotherapy; the 3·5-year

progression-free survival was 79·4%.44,61 Notably, the

combination of 12 cycles of venetoclax plus six cycles

obinutuzumab in the CLL14 trial reported 5-year

progression-free survival of only 41% in TP53-aberrant

CLL. Several trials are investigating combined BTK

inhibitors plus venetoclax with or without obinutuzumab

as a time-limited approach for patients with TP53-aberrant

CLL. In the CLL2-GIVe trial, 41 patients with previously

untreated TP53-aberrant CLL received the combination of

ibrutinib plus venetoclax plus obinutuzumab.75 After cycle

15, 66% of the patients had U-MRD (sensitivity 0·01%)

remission in the bone marrow and 3-year progression-free

survival was 79·9%. Longer follow-up of these trials is

needed to ascertain if a BTK inhibitor plus venetoclaxbased combination would be better than BTK inhibitor

monotherapy for TP53-aberrant CLL.

Role of chemoimmunotherapy in first-line treatment

Although the use of chemoimmunotherapy has declined

substantially for CLL, patients with IGHV-mutated CLL

can derive long-term remission and possibly cure after

fludarabine, cyclophosphamide, and rituximab.84 In a

trial conducted at MDACC, approximately 48% of

patients with IGHV-mutated CLL were in remission at

15 years after receiving first-line fludarabine,

cyclophosphamide, and rituximab, indicative of durable

remissions.84 Several trials have investigated combined

ibrutinib with chemoimmunotherapy for first-line

Participants

(N)

Median age

(range)

U-IGHV Del(17p) TP53 mutation Treatment Progression-free

survival

Ibrutinib (NIH trial)76 34 63 years

(33–82)

69% 94% NR Ibrutinib monotherapy 5 years, 70%

BTK inhibitor ± venetoclax ± CD20 monoclonal antibodies

(pooled analysis, MDACC trial)14

130 63 years

(36–88)

80% 80% 81% BTK inhibitor (ibrutinib 88%;

acalabrutinib 12%); CD20

monoclonal antibodies 22%;

venetoclax 29%

4 years, 73%

Ibrutinib ± CD20 monoclonal antibodies (pooled clinical trial

analysis)82

89 65 years

(33–87)

69% 53% 91% Ibrutinib (n=45); ibrutinib and

CD20 monoclonal antibodies

(n=44)

4 years, 79%

Acalabrutinib ± CD20 monoclonal antibodies (pooled clinical

trial analysis)83

64 NR NR NR NR Acalabrutinib ± obinutuzumab 4 years, 77%

Zanubrutinib (SEQUOIA trial, arm C)44,61 111 71 years

(42–87)

65% 99% 43% Zanubrutinib monotherapy 3·5 years, 79%

Zanubrutinib and venetoclax (SEQUOIA trial, arm D)76 49 65 years

(25–86)

88% 94% 92% Zanubrutinib and venetoclax 1 year, >95%

Venetoclax and obinutuzumab (CLL14 trial)15,45,108 25 NR 76% 68% 92% Venetoclax and obinutuzumab 6 years, ~22%

Ibrutinib and venetoclax (MDACC trial)64,65,69 27 65 years

(36–82)

80% 74% 70% Ibrutinib and venetoclax

(24 cycles combination)

5 years, 86%

Ibrutinib and venetoclax (CAPTIVATE trial, FD cohort)67,70 27 NR NR 74% 59% Ibrutinib and venetoclax

(12 cycles combination)

4·5 years, 45%

Ibrutinib, venetoclax, and obinutuzumab (CLL2-GIVe trial)75 41 62 years

(35–85)

78% 63% 95% Ibrutinib, venetoclax, and

obinutuzumab

3 years, 80%

Acalabrutinib, venetoclax, and obinutuzumab (DFCI trial)73,79 41 NR NR 76% 93% Acalabrutinib, venetoclax, and

obinutuzumab

NR

BTK=Bruton tyrosine kinase. NR=not reported. U-IGHV=unmutated immunoglobulin heavy chain variable region.

Table 3: Outcomes of selected first-line trials in del(17p) or TP53-mutated chronic lymphocytic leukaemia

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8 www.thelancet.com Published online July 25, 2024 https://doi.org/10.1016/S0140-6736(24)00595-6

therapy of CLL.85–88 A trial focusing only on a

chemosensitive subgroup (IGHV-mutated CLL without

del[17p] or TP53 mutation), combined 12 cycles of

ibrutinib with three cycles of fludarabine and

cyclophosphamide, and then (depending on patient

response) six or 12 cycles of obinutuzumab (iFCG

regimen), led to bone marrow U-MRD remission

(sensitivity 0·01%) in 44 (98%) of 45 patients, with a

6-year progression-free survival of 89·2%.85,89 However,

given the potential for toxicities with chemoimmunotherapy, including risk of therapy-related myelodysplastic

syndrome or acute myeloid leukaemia, we do not

recommend chemoimmunotherapy even for patients

with IGHV-mutated CLL, unless access or cost of

targeted therapies is a problem.

Selecting first-line therapy

The choice of first-line targeted therapy in CLL is between

continuous BTK inhibitors versus time-limited venetoclax

and obinutuzumab. There are positives and negatives of

the two approaches.90 Single-agent BTK inhibitors provide

easier initiation of therapy, little risk of tumour lysis

syndrome, and do not require intravenous infusion.

However, BTK inhibitors are recommended to be taken

continuously until progression and are associated with

BTK inhibitor-related adverse events. Although not

contraindicated, caution should be exercised in using BTK

inhibitors in patients with coronary artery disease,

uncontrolled atrial fibrillation, or need for long-term

anticoagulation. Venetoclax-based therapy provides for a

time-limited approach. Patients need to be closely

monitored for tumour lysis syndrome. Grade 3–4

neutropenia can occur in about 50% of patients. Risk of

tumour lysis syndrome is increased in patients with bulky

adenopathy and those with renal dysfunction. We offer

both these treatment approaches to patients and make a

therapy decision based on patient preference. As

mentioned, the presence of certain comorbidities can

mean that one approach is favoured over the other. Notably,

for patients with TP53-aberrant CLL, venetoclax and

obinutuzumab leads to suboptimal long-term remission,

and continuous BTK inhibitor therapy is currently the

preferred approach. Due to the better safety profiles of

second-generation BTK inhibitors (eg, acalabrutinib and

zanubrutinib) compared with ibrutinib, we prefer secondgeneration BTK inhibitors. In several countries, the

combination of ibrutinib and venetoclax is approved as a

time-limited therapy. Given that both ibrutinib and

venetoclax are oral drugs, these are logistically easier to

administer. Additionally, use of ibrutinib for a few months

before venetoclax initiation lowers the risk of tumour lysis

syndrome. Emerging data from ongoing clinical trials

exploring BTK inhibitor and venetoclax combinations

report high rates of U-MRD remission across all genomic

subgroups;47,48,64,67 however, the follow-up is relatively short

to comment on long-term durability, especially for patients

with TP53-aberrant CLL. Several ongoing trials are

investigating combination of second-generation BTK

inhibitors with BCL2 inhibitors (with or without

obinutuzumab) and long-term results from these trials are

awaited. We do not recommend use of chemoimmunotherapy for patients with CLL; however, in resourceconstrained settings where novel targeted therapies are not

available or affordable, chemoimmunotherapy can be

considered, especially for patients with IGHV-mutated

CLL without del(17p) or TP53-mutation.

Relapsed or refractory disease therapy

Selection of therapy for relapsed or refractory CLL largely

depends on previous therapies the patient received. It is

important to assess if the patient relapsed while actively

receiving therapy (such as progression while taking BTK

inhibitors) versus if the patient was off therapy at the

time of disease progression (such as progression after

completing time-limited venetoclax-based therapy, or

progression after BTK inhibitor was interrupted due to

an adverse event or medical complication). It is

important to note that just the evidence of disease

relapse alone, such as rise in absolute lymphocyte count

or small volume adenopathy, is not an indication to

initiate therapy for relapsed disease; patients with

relapsed or refractory CLL should also meet iwCLL

treatment indication before initiating therapy. Patients

who show signs of disease progression while on a BTK

inhibitor can have a rapid disease flare if the BTK

inhibitor is abruptly discontinued; for such patients, it is

recommended to overlap the BTK inhibitor with the next

line of therapy. Several potential therapy sequencing

scenarios are depicted in figure 3; clinical trial data for

some of these sequencing options are not yet available,

and additional treatment sequencing options could be

envisioned as CLL therapy continues to evolve. An

important aspect of figure 3 is the timeline regarding

therapy options for ten or more years, indicating success

in the treatment of patients with CLL.

Ibrutinib was initially approved for relapsed or

refractory CLL on the basis of data from the RESONATE

trial, in which patients with relapsed or refractory CLL

were randomly assigned to receive ibrutinib versus

ofatumumab.49,50 In the ibrutinib group, patients had

received a median of three previous lines of treatment;

the median progression-free survival was 44 months,

compared with 8 months for ofatumumab. Acalabrutinib

was investigated in the phase 3 ASCEND trial in patients

with CLL; patients were randomly assigned to receive

acalabrutinib versus either bendamustine and rituximab

or idelalisib plus rituximab.53,54 Acalabrutinib was

superior to both bendamustine and rituximab and

idelalisib plus rituximab groups for progression-free

survival. More recently, acalabrutinib (n=268) was

compared head-to-head with ibrutinib (n=265) in the

ELEVATE-RR open-label randomised trial in patients

with relapsed or refractory CLL and either del(11q) or

del(17p).59 The primary endpoint was non-inferiority of

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progression-free survival. Patients received a median of

two previous lines of therapy. The median follow-up was

40·9 months. The progression-free survival was similar

in both groups (median 38·4 months; acalabrutinib met

the non-inferiority for progression-free survival vs

ibrutinib) with lower rates of all-grade atrial fibrillation,

hypertension, and bleeding events for treatment with

acalabrutinib compared with ibrutinib. Zanubrutinib

(n=327) was also compared head-to-head with ibrutinib

(n=325) in the ALPINE open-label randomised trial in

patients with relapsed or refractory CLL.60 Unlike the

ELEVATE-RR trial, all genomic subgroups were

included in the ALPINE trial. The primary endpoint was

overall response rate. Patients received a median of one

previous line of therapy. With a median follow-up of

39 months, zanubrutinib led to statistically significant

improvement in progression-free survival compared

with ibrutinib; 3-year progression-free survival was

64·9% in the zanubrutinib group versus 54·8% in the

ibrutinib group (p=0·001).91 The rates of all-grade atrial

fibrillation were lower with zanubrutinib versus

ibrutinib, and the rates of hypertension and bleeding

events were similar. With the results of the ELEVATERR and ALPINE trials, second-generation BTK

inhibitors (eg, acalabrutinib and zanubrutinib) have

become the preferred BTK inhibitors for treatment of

patients with CLL.

Over the past several years, non-covalent BTK

inhibitors (also called reversible BTK inhibitors) were

developed, which do not bind to the cysteine 481 residue

of the BTK, and consequently have clinical activity in

patients who develop resistance to covalent BTK

inhibitors through BTK C481 mutation. Pirtobrutinib is

the first approved non-covalent BTK inhibitor, which

was approved in late 2023 in the USA for patients with

CLL who have received at least two previous lines of

therapy, including a BTK inhibitor and a BCL2

inhibitor.92,93 The BRUIN trial enrolled 247 patients with

relapsed or refractory CLL who all had previous covalent

BTK inhibitor exposure (190 [77%] had progression to

previous covalent BTK inhibitor, and 57 [23%] had

toxicity or another reason to discontinue covalent BTK

inhibitor), 100 (41%) of these patients had previous

venetoclax exposure and these patients received

pirtobrutinib monotherapy.92,93 The patient population

was heavily pretreated with a median of three previous

lines of therapy, and the majority of patients had highrisk genomics (85% IGHV-unmutated CLL and 47%

del[17p] or TP53-mutated CLL). The overall response

rate was 82% with a median progression-free survival

of 19·6 months. Among the patients who had previously

received both covalent BTK inhibitor and venetoclax

(n=100), the median number of previous lines of

therapy was five, the overall response rate was 79%, and

the median progression-free survival was 16·8 months.

The responses were independent of the BTK C481

mutation.

Venetoclax was evaluated in the phase 3 MURANO

trial in relapsed or refractory CLL; patients were

randomly assigned to bendamustine and rituximab

versus a 2-year fixed-duration regimen of venetoclax plus

rituximab.55 The median number of previous therapies

was one. Both progression-free survival and overall

survival were significantly superior for patients who

received venetoclax plus rituximab versus bendamustine

and rituximab. Among venetoclax and rituximab-treated

patients, those with IGHV-unmutated CLL had

significantly shorter progression-free survival compared

with IGHV-mutated CLL (5-year progression-free

survival 29% vs 73%, respectively; p<0·001).

PI3K inhibitors (eg, idelalisib and duvelisib) are

currently approved for relapsed or refractory CLL.94,95

Overall, the efficacy of PI3K inhibitors appears lower

compared with that reported for BTK inhibitors and

venetoclax in relapsed or refractory CLL in cross-trial

comparisons, in part due to early discontinuation of

PI3K inhibitors due to toxicities. Additionally, in the

ASCEND trial, acalabrutinib was noted to be superior to

combined idelalisib and rituximab.53,54 PI3K inhibitors

are associated with immune-mediated adverse events,

such as colitis and transaminitis, and patients should be

closely monitored for these complications. There is also

increased risk of infectious complications. In clinical

practice, PI3K inhibitors have a role in patients who are

refractory or intolerant to therapy with BTK inhibitors

and venetoclax.

Figure 3: Treatment sequencing scenarios

CAR T=chimeric antigen receptor T cell.cBTK=covalent Bruton tyrosine kinase. ncBTK=non-covalent Bruton tyrosine kinase.

BCL2 cBTK inhibitor

inhibitor

and CD20

A

B

C

• ncBTK inhibitor

• BCL2 inhibitor and CD20

• CAR T, others

BCL2 inhibitor and

CD20

cBTK inhibitor

• ncBTK inhibitor

• BCL2 inhibitor and CD20

• CAR T, others

• cBTK inhibitor or ncBTK inhibitor

• CAR T, others

BCL2

inhibitor

and CD20

BCL2 inhibitor and

CD20

0 1 2 3 4 5 6 7 8 9

Years

10 11 12 13 14 15

Scenarios

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10 www.thelancet.com Published online July 25, 2024 https://doi.org/10.1016/S0140-6736(24)00595-6

Chimeric antigen receptor (CAR) T-cell therapy

targeting CD19 was evaluated in several clinical trials in

relapsed or refractory CLL. In the TRANSCEND CLL 004

trial—the largest trial reported to date in patients with

relapsed or refractory CLL—patients received lisocabtagene maraleucel after undergoing lymphodepletion

with fludarabine and cyclophosphamide.96 117 patients

received lisocabtagene maraleucel with a median of five

previous lines of therapy, with all patients having

previously received a BTK inhibitor and 94 (80%) having

previously had venetoclax. The rate of complete

remission or complete remission with incomplete count

recovery among the efficacy-evaluable patients at dose

level 2 (100×10⁶ CAR+

T cells; n=87) was 18% with an

overall response rate of 47%. U-MRD (sensitivity 0·01%)

remission was reported in peripheral blood and bone

marrow in 64% and 59% of the 87 efficacy-evaluable

patients, respectively. The median progression-free

survival was 18 months. 10 (9%) patients had grade 3

cytokine release syndrome (none had grade 4 or 5

cytokine release syndrome); 21 (18%) had grade 3

neurotoxicity and 1 (1%) had grade 4 neurotoxicity.

The role of allogeneic stem cell transplantation has

declined for patients with CLL in the targeted therapy

era.97 We recommend referral for allogeneic stem cell

transplantation in young patients who did not respond

to, relapsed after initial response, or are intolerant to

both a BTK inhibitor and venetoclax (so-called doublerefractory or double-exposed group), especially if they

have TP53-aberrant CLL.

Complications and challenges of CLL or

CLL-directed therapies

Despite long-term remissions achieved with BTKinhibitor

and BCL2 inhibitor therapies, many patients eventually

relapse. For patients progressing on a covalent BTK

inhibitor, BTK and PLCG2 mutations have been

identified.98 Similarly, BCL2 mutations were associated

with venetoclax resistance.99 Knowledge of these mutations

at the time of disease progression can potentially help in

selecting a subsequent BTK inhibitor, as covalent and

non-covalent BTK inhibitors appear to have different

sensitivity to BTK inhibitor resistance mutations in

preclinical models.100–102 It is important to note that not all

patients will develop resistance mutations at the time of

relapse, indicative of alternative mechanisms of resistance.

Therapy-related myelodysplastic syndrome or acute

myeloid leukaemia can occur in 4–5% of patients receiving

chemoimmunotherapy, such as fludarabine,

cyclophosphamide, and rituximab, and these patients

have dismal outcomes.84,103 Richter transformation, most

commonly to diffuse large B-cell lymphoma, occurs in

5–10% of patients with CLL and remains an unmet

medical need with survival of fewer than 12 months with

chemoimmunotherapy, especially in patients where the

diffuse large B-cell lymphoma component is clonally

related to underlying CLL.104 Therapies used for CLL, such

as covalent BTK inhibitor, venetoclax, and non-covalent

BTK inhibitor (eg, pirtobrutinib), have shown activity in

patients with Richter transformation in clinical trials.105,106

Checkpoint inhibitors, such as those targeting PD1 and

PD-L1, are also being investigated in patients with Richter

transformation.107,108 Allogeneic stem cell transplantation

remains the only curative modality for patients with

Richter transformation.

Conclusions

The therapeutic landscape of CLL has changed remarkably

in the last decade with development of targeted therapies

that have largely supplanted chemoimmunotherapy.

Currently, BTK inhibitors and BCL2 inhibitors remain

the two most active classes of drugs for CLL and have

shown superior outcomes compared with chemoimmunotherapy in several randomised trials. Whether a

sequential approach of BTK inhibition followed by BCL2

inhibition (or vice versa) versus a concurrent doublet

combination of BTK and BCL2 inhibition, or a triplet

combination (BTK inhibitor plus BCL2 inhibitor plus a

CD20 monoclonal antibody) is best for long-term

outcomes remains to be established. Therapies active in

relapsed or refractory CLL, such as non-covalent BTK

inhibitors, are now being pursued in earlier lines of

therapy, including first-line treatment of CLL.

Contributors

All authors participated in the development and review of the manuscript,

and reviewed and approved the final version of the manuscript.

Declaration of interests

NJ received funding (to institution) from Pharmacyclics, AbbVie,

Genentech, AstraZeneca, Bristol Myers Squibb, Pfizer, ADC Therapeutics,

Cellectis, Adaptive Biotechnologies, Precision Biosciences, Fate

Therapeutics, Kite–Gilead, Mingsight, Takeda, Medisix, Loxo Oncology,

Novalgen, Dialectic Therapeutics, Newave, Novartis, Carna Biosciences,

Sana Biotechnology, and Kisoji Biotechnology; and consulting and

honorarium fees from Pharmacyclics, Janssen, AbbVie, Genentech,

AstraZeneca, Bristol Myers Squibb, Adaptive Biotechnologies,

Kite–Gilead, Precision Biosciences, Beigene, Cellectis, MEI Pharma,

Ipsen, CareDX, Eli Lilly, MingSight, and Novalgen. WGW received

funding (to institution) from AstraZeneca–Acerta Pharma, Cyclacel,

Genentech, Gilead Sciences, GlaxoSmithKline, Novartis, Janssen, Juno

Therapeutics, KITE Pharma, Loxo Oncology, Miragen, Oncternal

Therapeutics, Pharmacyclics, Sunesis, and Xencor; personal fees from

Cylacel, Loxo, Novartis, and Xencor; and travel support from AbbVie,

Acerta Pharma, Genentech, Gilead Sciences, Janssen Biotech, Juno

Therapeutics, Kite Pharma, Oncternal Therapeutics, and Pharmacyclics.

SO received funding (to institution) from Alliance, AstraZeneca, Caribou

Biosciences, Gilead, Kite, Mustang Bio, Nurix Therapeutics, Pfizer,

Pharmacyclics, Regeneron, and TG Therapeutics; and consulting and

honorarium fees from AbbVie, AstraZeneca, Autolus, Beigene, BMS,

Eli Lilly, GlaxoSmithKline, Janssen, Johnson & Johnson, Merck, Pfizer,

Pharmacyclics, TG Therapeutics, and Vanian Group.

Acknowledgments

NJ is supported by the LLS Scholar in Clinical Research Award.

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