2025-09-24
CLL: ESMO declares the end of chemotherapy, focus on targeted therapies
Oncology
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.
Chemotherapy is out in most cases. Two major strategies are now recommended:
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.
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.
When a relapse occurs:
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.
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.
About the author – Lila Rouland
With dual expertise in science and marketing, Lila brings her knowledge to the service of healthcare innovation. After five years in international academic research, she transitioned into medical and scientific communication within the pharmaceutical industry. Now working as a medical writer and content developer, she is committed to highlighting scientific knowledge and conveying it to healthcare professionals with clarity and relevance.
#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
When a relapse occurs:
- 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
Last press reviews
By Ana Espino | Published on october 1st, 2025 | 3 min read<br><br>...
Gallstones: Genetics strikes back!
By Ana Espino | Published on september 30, 2025 | 3 min read