Lymph Node Microenvironment Modifications in Patients With CLL Treated With Venetoclax-based Regimens

CLL subjects who should receive treatment with a venetoclax-based regimen as per standard of care will be enrolled into this trial, after providing informed consent.

The following evaluations will be performed baseline before starting treatment:

Baseline assessments:

In addition to standard staging procedures before treatment initiation, including blood tests and BM aspirate and biopsy, the following procedures will be performed per protocol:

• Peripheral blood sample drawing for pharmacodynamics studies, MRD assessment and cfDNA evaluation
• Ultrasound-guided lymph node CNB
• Tailored ultrasound evaluation of nodal sites and spleen
• Bone marrow MRD sample drawing (optional) The nodal site for the biopsy will be selected based on the size (the largest nodal lesion will be considered) and the procedure feasibility (only superficial cervical, axillary or inguinal lymph nodes will be considered suitable for biopsy).

On treatment assessments:

Peripheral blood sampling and ultrasound-guided lymph node CNB will be repeated in patients on venetoclax-based therapy:

• 7 days after completion of venetoclax ramp up phase,
• +12 months after completion of venetoclax ramp-up phase. Patients with residual lymph nodes that are not suitable for ultrasound-guided lymph node CNB will continue the ultrasound monitoring only

Patients will follow an intensive ultrasound monitoring schedule, which requires tailored ultrasound evaluation being repeated at the following timepoints:

• 4 weeks after venetoclax ramp-up completion
• Every 2 months thereafter until disease progression or unacceptable toxicity leading to permanent treatment discontinuation.

Assessments at progression:

A tailored ultrasound of nodal sites and spleen will be performed within 2 weeks from the first signs and/or symptoms of suspected progression. US assessment can be delayed at Investigator's discretion in case pseudo-progression is suspected based on potentially confounding concomitant conditions, e.g. infection.

In progressive cases, the same assessments (including BM aspirate and biopsy) will be repeated at the time of disease progression.

In patients progressing with bulky lymph nodes an incisional lymph node biopsy (instead of an ultrasound-guided CNB) will be performed to exclude Richter's transformation as per standard of care.