By Lila Rouland | Published September 24, 2025 | 3 min read
#ChronicLymphocyticLeukemia
#TargetedTherapies #ESMO
Clinicians
had long debated: should high-risk CLL be treated earlier, even without
symptoms? The idea was appealing—using targeted therapies at early stages to
control the disease before it progresses. This was precisely tested in the
CLL12 trial, which compared ibrutinib (a BTK inhibitor) with placebo in
early-stage patients carrying
poor-prognosis factors (unmutated IGHV,
cytogenetic abnormalities). The outcome was clear: while ibrutinib delayed time
to first treatment (progression-free survival), it offered no overall survival
benefit.
Treating
CLL too early exposes patients to adverse effects (hypertension, arrhythmias,
bleeding) and the risk of resistance, without extending life. ESMO therefore
maintains the “watch and wait” strategy: regular monitoring, with
treatment only when the disease becomes active.
Targeted
therapies: the new first-line standard
Chemotherapy is out in most cases. Two major strategies are now recommended:
- Continuous therapy: indefinite treatment with BTK
inhibitors (ibrutinib, acalabrutinib, zanubrutinib).
- Time-limited therapy: fixed-duration courses, such
as venetoclax + obinutuzumab (12 cycles) or ibrutinib + venetoclax (12–15
cycles, sometimes MRD-guided).
Chemo-immunotherapy
(FCR, bendamustine, or chlorambucil) now has only a marginal role. It is
reserved for a small group of carefully selected patients with favorable
genetic profiles (mutated IGHV, no TP53 abnormalities, simple karyotype), and
only where targeted therapies are inaccessible.
Next-generation
BTK inhibitors: equally effective, safer
Ibrutinib is no longer the only option. Its successors, acalabrutinib and
zanubrutinib, offer comparable efficacy with a better cardiovascular safety
profile—less atrial fibrillation, less hypertension—making them preferable for
older patients or those with cardiac risk. These are now the preferred options in real-world practice. Venetoclax is the star of “time-limited” treatments.
The GAIA-CLL13 and CLL14 trials transformed practice: venetoclax + obinutuzumab
clearly outperformed chemo-immunotherapy. More patients achieved undetectable
minimal residual disease (MRD), and progression-free survival was extended.
Adding ibrutinib to this duo further increases efficacy (92% undetectable MRD!), but at the cost of more frequent severe infections. As a result: caution is advised before adopting this triple combination on a large scale.
Relapse: targeted therapy dominates
- After chemotherapy: venetoclax
+ rituximab (24 months) or a BTK inhibitor continuously.
- After a BTK inhibitor: switch
to venetoclax.
- After venetoclax: switch back
to a BTK inhibitor.
For highly resistant cases, a new player has emerged:
pirtobrutinib,
a non-covalent BTK inhibitor, already approved in the U.S. for
double-refractory patients.
MRD: the
new therapeutic compass
Minimal residual disease (MRD) is becoming a key tool. In the FLAIR trial, the
duration of ibrutinib-venetoclax therapy was personalized according to MRD
status, with spectacular results in both progression-free and overall survival.
Tomorrow, MRD could guide the duration of targeted therapy, paving the way for
even more individualized medicine.
The 2024
ESMO update confirms a revolution: targeted therapies are replacing chemotherapy in CLL. Time-limited
options are gaining ground, promising shorter, better-tolerated treatments
adapted to each patient’s genetic profile. The future? CLL monitored closely
through MRD, with personalized strategies and ever-more precise therapies.
Read next: Chronic myelomonocytic leukemia: at the molecular roots of inflammation
About the author – Lila Rouland
Doctor of Oncology, specialized in Biotechnology and Management
