Venetoclax–Rituximab Retreatment in CLL: What a 100% Response Rate Means for Patients

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Chronic lymphocytic leukemia (CLL) treatment has advanced significantly over the past decade, particularly with the introduction of targeted therapies such as BCL2 inhibitors and monoclonal antibodies. Now, new research offers promising evidence that patients who previously responded to venetoclax and rituximab (VenR) may benefit from retreatment with the same combination after disease progression.

A recent study published in HemaSphere reports a remarkable 100% overall response rate (ORR) among patients retreated with VenR, along with prolonged progression-free survival (PFS). These findings suggest that fixed-duration venetoclax-based therapy may not only induce deep initial responses but also preserve sensitivity to retreatment.

Background: Venetoclax and Rituximab in CLL

Venetoclax is a BCL2 inhibitor that promotes apoptosis (programmed cell death) in CLL cells. Rituximab is a monoclonal antibody targeting CD20 on B lymphocytes. Together, this combination has become a well-established treatment option for relapsed or refractory CLL.

The phase 1b M13-365 trial (NCT01682616) originally evaluated this combination and allowed patients to discontinue therapy if they achieved a deep response. This design enabled investigators to later study retreatment outcomes when patients experienced disease progression after stopping therapy.

Study Overview: Phase 1b M13-365 Trial

This analysis included nine patients (four male and five female) enrolled between August 2012 and May 2014. Patient characteristics included:

• Age range: 58–79 years
• Prior therapies: 1–4 lines
• Initial therapy duration: 139 to 1210 days
• Retreatment duration: 130 to 2037 days

Before retreatment:

• Median lymphocyte count: 22.5 × 10⁹/L
• Median maximum lymph node size: 34.8 mm

Genomic features included:

• One patient with del(17p)
• One patient with a TP53 mutation
• Two patients with IGHV-mutated disease

These diverse genomic backgrounds make the results particularly noteworthy.

Initial Response to Venetoclax–Rituximab

During initial therapy:

• 6 patients achieved a complete response (CR)
• 2 achieved CR with incomplete recovery (CRi)
• 1 achieved partial response (PR)

Importantly, many patients achieved undetectable minimal residual disease (uMRD), which is strongly associated with improved long-term outcomes.

Criteria for Retreatment

Disease progression after initial therapy was defined as:

• Two consecutive MRD measurements >10⁻⁴
  OR
• A single MRD measurement >10⁻³

Prior to retreatment, confirmation included:

• CT scan or MRI
• Bone marrow biopsy

Retreatment protocol:

• 5-week venetoclax ramp-up
• 400 mg daily oral venetoclax
• Rituximab was initiated at week 6
  • 375 mg/m² on day 1
  • 500 mg/m² monthly for 5 months

Retreatment Results: 100% Response Rate

All nine patients responded to retreatment:

• 3 achieved complete response (CR)
• 6 achieved partial response (PR)

This resulted in a 100% overall response rate.

Progression-Free Survival (PFS)

The durability of response was particularly striking:

• Median PFS from first VenR treatment: 9.5 years
• Median PFS from retreatment: 4.9 years

Patients remained off treatment for a median of 38.4 months before disease progression. Four patients remain progression-free more than one year after retreatment and are currently off therapy.

These findings suggest that fixed-duration therapy does not compromise long-term disease control and may preserve retreatment effectiveness.

Minimal Residual Disease (MRD) Findings

Before retreatment:

• Most patients were MRD-positive in bone marrow and/or peripheral blood
• Only one patient maintained uMRD status

After retreatment, patients again achieved meaningful responses, reinforcing the idea that deep initial responses may maintain disease sensitivity.

The study also demonstrated that progression-free survival off therapy among patients achieving deep response was comparable to that of those who remained on continuous treatment.

Genomic Mutation Analysis

An important subanalysis examined BCL2 mutations:

• 6 patients previously developed BCL2 mutations after earlier venetoclax-based therapy
• No detectable BCL2 mutation was found in 4 patients before retreatment
• 2 patients tested after retreatment also showed no mutation

Additionally:

• No patients tested positive for del(17p) prior to retreatment
• One patient tested positive for a TP53 mutation

These results suggest that resistance mutations may not universally persist or prevent retreatment response.

Why These Results Matter

This study is significant for several reasons:

1. It provides the first prospective evidence that CLL responses can be maintained off treatment after a deep initial response.
2. It demonstrates that retreatment with venetoclax and rituximab remains highly effective.
3. It supports the strategy of fixed-duration therapy rather than indefinite continuous treatment.
4. It suggests that limited exposure may reduce the risk of future resistance.

Unlike continuous therapy models, fixed-duration treatment allows patients meaningful time off therapy, potentially improving quality of life and reducing cumulative toxicity.

Comparison With Other Venetoclax Studies

The findings align with retreatment data from:

• The MURANO trial final analysis
• Blood Advances retreatment study (2022)
• Genomic resistance studies on BCL2 mutation emergence

However, this analysis reports a longer median time off therapy compared with prior research, strengthening the argument for time-limited therapy strategies.

Clinical Implications

For clinicians, this study suggests:

• Retreatment with VenR is a viable option after progression off therapy.
• Deep responses (CR or uMRD) are strong predictors of durable off-treatment remission.
• Fixed-duration therapy does not necessarily compromise future retreatment efficacy.

For patients, this offers hope that:

• Achieving deep remission may allow extended treatment-free intervals.
• Retreatment remains an effective strategy if relapse occurs.
• Long-term disease management may not require continuous therapy.

Limitations

• Small sample size (9 patients)
• Phase 1b study design
• Longer-term follow-up is still ongoing

Despite these limitations, the 100% response rate and nearly 5-year median PFS after retreatment are highly encouraging.

Conclusion

The phase 1b M13-365 study provides compelling evidence that retreatment with venetoclax and rituximab is both safe and effective in patients with chronic lymphocytic leukemia who previously achieved deep responses and later experienced disease progression.

With a 100% response rate and durable progression-free survival, these findings support the growing role of fixed-duration therapy in CLL treatment strategies.

As research continues, this approach may help reduce long-term resistance while preserving quality of life through meaningful treatment-free intervals.

References

1. Brander DM, Roberts AW, Kipps TJ, et al. Retreatment with venetoclax and rituximab following disease progression while off therapy in patients with chronic lymphocytic leukemia. HemaSphere. 2025;9(12):e70284. doi:10.1002/hem3.70284
2. Kater AP, Harrup R, Kipps TJ, et al. The MURANO study: final analysis and retreatment/crossover substudy results of VenR for patients with relapsed/refractory CLL. Blood. 2025;145(23):2733‐2745. doi:10.1182/blood.2024025525
3. Thompson MC, Harrup RA, Coombs CC, et al. Venetoclax retreatment of patients with chronic lymphocytic leukemia after a previous venetoclax-based regimen. Blood Advances. 2022;6(15):4553‐4557. doi:10.1182/bloodadvances.2022007812
4. Popovic R, Dunbar F, Lu C, et al. Identification of recurrent genomic alterations in the apoptotic machinery in chronic lymphocytic leukemia patients treated with venetoclax monotherapy. Am J Hematol. 2022;97(2):e47‐e51.
5. Blombery P, Thompson ER, Nguyen T, et al. Multiple BCL2 mutations co-occurring with Gly101Val emerge in chronic lymphocytic leukemia progression on venetoclax. Blood. 2020;135(10):773‐777.