Randomized study of rituximab plus short‑term vs extended venetoclax in patients with relapsed or refractory chronic lymphocytic leukemia

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What is this study about?

The study focuses on adults whose disease has returned after earlier therapy (“relapsed”) or has not responded (“refractory”). The conditions being examined are chronic lymphocytic leukemia and small lymphocytic lymphoma. The treatment combines an infusion of rituximab, given in six treatment cycles, with an oral tablet called venetoclax. Participants will receive the same short‑term combination of the two drugs, after which venetoclax may be stopped or continued for a longer period.

The purpose is to determine whether continuing venetoclax for a longer time leads to a longer interval without disease worsening compared with stopping the drug after the short course. After random assignment, each participant follows the same initial six cycles, then either discontinues venetoclax or remains on it for the extended schedule, with regular clinic visits to monitor safety and disease status.

During the trial, patients take the venetoclax tablets daily, undergo blood tests to look for cancer cells, and report any side effects they experience. The study also tracks overall health and quality of life through questionnaires, and it continues until the final planned follow‑up visit for each participant.

1 randomization to treatment arm

after you join the study you are assigned by randomization to either the short‑duration arm or the long‑duration arm.

the assigned arm determines the total length of oral medication venetoclax you will receive after the initial combination period.

2 start rituximab infusions

you receive an intravenous infusion of rituximab once every 4 weeks.

a total of six infusions (six cycles) are given, covering approximately 24 weeks.

3 begin venetoclax ramp‑up

on the first day of the first rituximab cycle you start oral venetoclax at a low dose.

the dose is increased each week: week 1 – 20 mg daily, week 2 – 50 mg daily, week 3 – 100 mg daily, week 4 – 200 mg daily, and from week 5 onward 400 mg daily.

4 continue venetoclax daily

after the ramp‑up you continue taking 400 mg of venetoclax each day.

if you are in the short‑duration arm you continue for a total of six cycles (approximately 24 weeks).

if you are in the long‑duration arm you continue for a total of twenty‑six cycles (approximately 104 weeks).

5 regular monitoring visits

throughout treatment you attend clinic visits every 4 weeks to have blood tests, safety assessments, and disease evaluations.

these visits allow the study team to check how you are responding to the medicines and to monitor for any side effects.

6 completion of treatment

when the assigned number of venetoclax cycles is finished, you stop taking the medication.

the six rituximab infusions are already completed after the first 24 weeks.

7 post‑treatment follow‑up

after stopping treatment you continue to be seen at scheduled intervals for up to week 84 after randomization.

these follow‑up visits include blood tests to assess disease status and overall health.

Who Can Join the Study?

Must have a confirmed diagnosis of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) that has either returned after treatment (relapsed) or did not respond to treatment (refractory) following at least one previous systemic (whole‑body) therapy.
Must have had a test for the TP53 gene mutation after the most recent treatment (TP53 mutation is a change in a gene that can affect how the disease behaves).
Must have had a test for the del17p mutation after the most recent treatment (del17p means a small piece of chromosome 17 is missing, which can influence treatment response).
Must be able and willing to follow the study visit schedule and all other protocol requirements.
Must sign a written informed consent (a document showing you understand the study and agree to take part).
Must be capable of giving informed consent (able to understand the information and make a decision).
Must need treatment according to the IWCLL 2018 criteria (the guidelines doctors use to decide when treatment for CLL/SLL is required).
Must be at least 18 years old.
Must have a WHO performance status of 0‑3 (a scale of how well you can carry out daily activities, where 0 is fully active and 3 means limited ability), and a score of 3 is allowed only if it is caused by CLL/SLL.
Must have adequate bone marrow (BM) function, meaning:
- Hemoglobin (the protein that carries oxygen in the blood) greater than 5.0 mmol/L, unless low because the disease is in the bone marrow.
- Absolute neutrophil count (a type of white blood cell) greater than 0.75 × 10⁹/L, unless low because of disease involvement.
- Platelet count (cells that help blood clot) greater than 30 × 10⁹/L, unless low because of disease involvement.
Must have kidney function measured by estimated glomerular filtration rate (eGFR) or creatinine clearance (CrCl) of at least 30 mL/min (these tests show how well the kidneys filter waste).
Must have adequate liver function, meaning:
- AST (aspartate transaminase) and ALT (alanine transaminase) levels no more than three times the upper limit of normal (ULN).
- Bilirubin level no more than 1.5 times ULN, unless the increase is due to Gilbert’s syndrome or a controlled autoimmune hemolytic anemia.
Must test negative for hepatitis B (both surface antigen and core antibody) and hepatitis C antibodies; if any test is positive, a follow‑up PCR test (a very sensitive test that looks for the virus’s genetic material) must be negative before enrollment.
Must have had the IGHV mutation status assessed at least once (IGHV is a gene region that helps doctors understand the disease’s behavior).

Who Cannot Join the Study?

If your CLL has changed into a more aggressive form called Richter’s transformation, you cannot join.
If you are currently receiving cancer‑fighting (anti‑neoplastic) drugs as part of another clinical study, you cannot join.
If personal, family, mental‑health, social or travel circumstances would make it hard for you to follow the study plan and attend appointments, you cannot join.
If you have taken the study drug venetoclax in the past 24 months, or if your disease got worse while on venetoclax before, you cannot join.
If your disease has spread to the brain or spinal cord (the central nervous system), you cannot join.
If you have another active cancer (besides CLL/SLL) that needs whole‑body (systemic) treatment, is not being treated to cure, or is getting worse after treatment intended to cure it, you cannot join.
If you have ever had a confirmed case of progressive multifocal leukoencephalopathy (PML), a rare brain infection, you cannot join.
If you are allergic to medicines called xanthine oxidase inhibitors or rasburicase, you cannot join.
If you have had a severe allergic reaction (hypersensitivity or anaphylaxis) to any of the study medicines, you cannot join.
If you have serious heart problems such as ongoing abnormal heart rhythms (arrhythmias) that need long‑term treatment, congestive heart failure, or chest pain from reduced blood flow (ischemic heart disease) that are considered severe, you cannot join.
If you have serious lung disease that makes breathing difficult (severe pulmonary dysfunction), you cannot join.
If you have serious brain or mental‑health disorders (severe neurological or psychiatric disease), you cannot join.
If you currently have a fungal, bacterial, or viral infection that needs whole‑body (systemic) medication, you cannot join.
If you have advanced liver disease classified as Child‑Pugh C, you cannot join.
If you have another serious medical problem that is not well controlled (for example uncontrolled diabetes, infection, high blood pressure, etc.), you cannot join.
If you are known to be HIV‑positive, you cannot join.
If you cannot swallow pills or have stomach/intestine problems (gastrointestinal disease) that would prevent the medicine from being absorbed, you cannot join.
If you are pregnant or breastfeeding, you cannot join.
If you are able to have children and are not using reliable birth control (or are not permanently unable to have children), you cannot join.
If you have already taken part in the HO139 or HO140 CLL studies and are eligible and willing to join the HO159 CLL study, you cannot join.

Where you can join this trial?

Verified and Recommended Sites

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Verified Sites

Site Name	City	Country	Status
Zuyderland Medisch Centrum Stichting	Geleen	The Netherlands

Other Sites

Site Name	City	Country
Ziekenhuis Gelderse Vallei Stichting	Ede	The Netherlands
Haga Hospital	Hague	The Netherlands
Universitair Medisch Centrum Utrecht	Utrecht	The Netherlands
Maasstad Ziekenhuis Stichting	Rotterdam	The Netherlands
St. Antonius Ziekenhuis	Nieuwegein	The Netherlands
Deventer Ziekenhuis	Deventer	The Netherlands
Reinier de Graaf Groep	Delft	The Netherlands
Stichting Treant Ziekenhuiszorg	Emmen	The Netherlands
Bravis Ziekenhuis	Roosendaal	The Netherlands
Slingeland Ziekenhuis	Doetinchem	The Netherlands
Noordwest Ziekenhuisgroep Stichting	Alkmaar	The Netherlands
Isala Klinieken Stichting	Zwolle	The Netherlands
Groene Hart Ziekenhuis	Gouda	The Netherlands
Jeroen Bosch Ziekenhuis Stichting	s-Hertogenbosch	The Netherlands
Amphia Hospital	Breda	The Netherlands
Albert Schweitzer Ziekenhuis	Dordrecht	The Netherlands
Ziekenhuis Rivierenland	Tiel	The Netherlands
Spaarne Gasthuis	Hoofddorp	The Netherlands
Medisch Spectrum Twente	Enschede	The Netherlands
Diakonessenhuis Stichting	Utrecht	The Netherlands
Elkerliek Ziekenhuis	Helmond	The Netherlands
ZorgSaam Ziekenhuis	Terneuzen	The Netherlands
Ziekenhuis St Jansdal	Harderwijk	The Netherlands
Ikazia Ziekenhuis	Rotterdam	The Netherlands
Het Van Weel-Bethesda Ziekenhuis	Dirksland	The Netherlands
Bernhoven B.V.	Uden	The Netherlands
Rode Kruis Ziekenhuis B.V.	Beverwijk	The Netherlands
Lvonljglem Zscsygnfab Ruyztcfj	Roermond	The Netherlands
Mgsjabjdfbnixg Prcrvoo Bxsw	Beugen	The Netherlands
Semfsfg	Geldrop	The Netherlands
Slu Erbzbmqcg Hxuvtnfd Tzvbtml	Tilburg	The Netherlands
Rcxfmafpa Zwvqhdklvh Sxkhnxaze	Arnhem	The Netherlands
Sivywejnu Mpobbam Zlajectbfy	Groningen	The Netherlands
Bydtxwn Zqylgwppjx	Gorinchem	The Netherlands

Trial status

Country	Status	Recruitment Start
The Netherlands	Not yet recruiting	15.06.2026

Trial locations

Investigated drugs:

Venetoclax

Venetoclax is an oral medicine taken in tablet form. It works by blocking a protein that helps cancer cells survive, so the leukemia cells are more likely to die. In this study, patients receive venetoclax together with rituximab for six cycles, and then continue taking venetoclax for either a longer period (about 20 cycles) or stop the drug, to see which approach keeps the disease from getting worse longer.

Rituximab is given by infusion into a vein. It is an antibody that attaches to a marker on the surface of many leukemia cells, marking them for destruction by the body’s immune system. In this trial, all participants receive six cycles of rituximab at the start of treatment, and it is combined with venetoclax to help control the disease.

Investigated diseases:

Relapsed or refractory small lymphocytic lymphoma – This is a blood cancer in which abnormal small lymphocytes build up in lymph nodes, bone marrow, and sometimes the spleen. “Relapsed” means the disease has returned after a period of improvement, while “refractory” means it has not responded to earlier treatment. The abnormal cells may slowly increase in number, causing the lymph nodes to enlarge. Over time, more of the bone marrow can become involved, reducing normal blood cell production. The condition can progress gradually, with symptoms becoming more noticeable as the disease spreads.
Relapsed or refractory chronic lymphocytic leukemia – This disease involves an excess of mature B‑cell lymphocytes circulating in the blood and residing in bone marrow. “Relapsed” indicates the leukemia has come back after a response, and “refractory” indicates it did not respond to prior therapy. The number of abnormal cells can rise steadily, leading to higher lymphocyte counts. The disease may expand to affect the lymph nodes, spleen, and bone marrow, lowering normal blood cell levels. Its course is typically slow, with gradual worsening of blood counts and organ involvement.

Trial ID:

2025-524283-38-00

Protocol code:

HOVON 182 CLL

Trial Phase:

Therapeutic confirmatory (Phase III)

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Randomized study of rituximab plus short‑term vs extended venetoclax in patients with relapsed or refractory chronic lymphocytic leukemia

What is this study about?

Who Can Join the Study?

Who Cannot Join the Study?