How a fixed-duration, chemotherapy-free approach revolutionized care for relapsed/refractory chronic lymphocytic leukemia
For decades, the diagnosis of relapsed or refractory chronic lymphocytic leukemia (CLL) carried with it a cycle of continuous treatment that dominated patients' lives. The paradigm shifted when the groundbreaking MURANO trial demonstrated that a fixed-duration, chemotherapy-free approach could not only match but surpass the efficacy of traditional regimens—giving patients meaningful treatment breaks without compromising outcomes 2 5 .
"The MURANO trial established venetoclax plus rituximab (VenR) as a transformative option that has since changed treatment guidelines and patient expectations worldwide."
The implications of MURANO extend far beyond the clinical trial results. For patients facing relapsed CLL, this research introduced the revolutionary concept of time-limited therapy—a predetermined treatment period followed by a break from medications—while maintaining long-term disease control. The recently published final analysis with seven years of follow-up data has cemented VenR's position in the CLL treatment arsenal, showing unprecedented survival benefits and introducing the possibility of successful retreatment for recurring disease 2 5 .
Patients Enrolled
Median Follow-up
Median PFS with VenR
7-Year OS Rate
Chronic lymphocytic leukemia (CLL) is the most common adult leukemia in Western countries, characterized by the progressive accumulation of dysfunctional mature B lymphocytes in the blood, bone marrow, and lymphoid tissues 3 . Typically diagnosed in older adults (median age 71 years), CLL has a highly variable clinical course—some patients remain asymptomatic for years without requiring treatment, while others experience rapid disease progression with debilitating symptoms like severe fatigue, enlarged lymph nodes, and recurrent infections .
Chemoimmunotherapy regimens were once standard, effectively controlling disease but causing significant side effects and eventually losing effectiveness as cancer developed resistance.
Targeted therapies—specifically drugs designed to block specific proteins that CLL cells need to survive—represented a major advancement with superior efficacy and manageable side effects 3 .
The VenR combination brings together two drugs with complementary mechanisms of action that create a powerful synergistic effect against CLL cells.
Targets the BCL-2 protein, a critical "survival protein" that prevents cancer cells from undergoing their normal death process (apoptosis). CLL cells produce excess BCL-2, allowing them to resist death and accumulate in the body. By specifically inhibiting BCL-2, venetoclax directly triggers apoptosis in the cancer cells, effectively "unleashing" their natural self-destruct mechanism 4 .
Is a monoclonal antibody that targets the CD20 protein found on the surface of both normal and cancerous B-cells. When rituximab binds to CD20, it marks these cells for destruction by the body's immune system through several mechanisms, including antibody-dependent cellular cytotoxicity (ADCC) and complement-mediated cytotoxicity 7 .
When combined, these drugs create a powerful one-two punch: venetoclax directly triggers cancer cell death from within, while rituximab helps the immune system identify and eliminate these cells from the outside. This synergistic effect explains the remarkable effectiveness of the combination observed in the MURANO trial.
The MURANO trial was a global, phase 3, open-label study conducted across multiple medical centers worldwide, designed to compare the efficacy and safety of the VenR combination against the then-standard chemoimmunotherapy regimen of bendamustine plus rituximab (BR) in patients with relapsed/refractory CLL 2 5 .
The trial enrolled 389 adult patients with relapsed or refractory CLL who had received between 1-3 prior lines of therapy. Participants were required to have adequate bone marrow, renal, and hepatic function, and an ECOG performance status of 0 or 1 (indicating they were fully active or restricted in physically strenuous activity but ambulatory) 5 .
The study employed rigorous randomization, assigning 194 patients to the VenR arm and 195 to the BR arm, ensuring balanced baseline characteristics between the two groups.
Patients received venetoclax with a standard 5-week ramp-up period (gradually increasing from 20mg to the target 400mg daily dose to minimize tumor lysis risk), then continued at 400mg daily for a total of 2 years. Rituximab was administered monthly for the first 6 cycles (375 mg/m² in cycle 1, then 500 mg/m² in cycles 2-6) 1 7 .
Patients received standard bendamustine (70 mg/m² on days 1-2 of each cycle) plus rituximab (at the same dosing as the VenR arm) for 6 cycles only 5 .
Investigator-assessed progression-free survival (PFS)
Overall survival (OS), overall response rate (ORR), and minimal residual disease (MRD) negativity rates 5
Regular comprehensive monitoring using advanced imaging, blood tests, and bone marrow biopsies to assess treatment response and MRD status
The final analysis of the MURANO trial, published after a median follow-up of 7 years, revealed unprecedented long-term benefits for patients receiving the VenR combination compared to standard chemoimmunotherapy 2 5 .
| Endpoint | VenR Arm | BR Arm | Hazard Ratio (HR) | P-value |
|---|---|---|---|---|
| Median PFS | 54.7 months | 17.0 months | 0.23 | < 0.0001 |
| 7-Year PFS Rate | 23.0% | 0% | - | - |
| 7-Year OS Rate | 69.6% | 51.0% | 0.53 | 0.0002 |
| Median OS | Not Reached | 87.8 months | - | - |
| Overall Response Rate | 87.5% (in BTKi-pretreated) 1 | - | - | - |
| MRD Status at End of Treatment | Median PFS from EOT | Statistical Significance |
|---|---|---|
| uMRD with no PD (n=83) | 52.5 months | P < 0.0001 |
| Detectable MRD (n=35) | 18.0 months | - |
| Patient Group | Median PFS | Best Overall Response Rate | uMRD Rate after Retreatment |
|---|---|---|---|
| VenR Retreatment (n=25) | 23.3 months | 72.0% | 8/25 patients (32%) |
| Crossover from BR (n=9) | 26.7 months | 88.9% | 6/9 patients (67%) |
While the VenR combination demonstrated superior efficacy, managing its safety profile was crucial for successful implementation in clinical practice.
The most frequent adverse event observed was neutropenia (low white blood cell count), with approximately half of patients experiencing grade 3 or 4 neutropenia during treatment 1 7 . This was generally manageable with growth factor support such as granulocyte colony-stimulating factor (G-CSF).
Other notable side effects included increased risk of infections (common to most CLL treatments) and mild gastrointestinal symptoms like diarrhea, which typically responded well to standard medications 7 .
The incidence of tumor lysis syndrome—a potential risk when rapidly destroying cancer cells—was effectively minimized through the mandatory 5-week venetoclax ramp-up and appropriate prophylactic measures 1 .
Compared to continuous therapies, the fixed-duration nature of VenR allowed for treatment breaks that resulted in meaningful recovery of the immune system. An exploratory analysis presented at the American Society of Hematology meeting in 2022 showed recovery of immunoglobulin levels (IgA, IgG, and IgM) after treatment completion, suggesting that time off therapy allows for some degree of immune reconstitution 7 .
The MURANO trial's final analysis has firmly established VenR as a standard of care for patients with relapsed/refractory CLL, including those previously treated with covalent BTK inhibitors 1 . The demonstrated 7-year overall survival benefit and the possibility of successful retreatment have provided clinicians with valuable flexibility in sequencing therapies for this chronic condition.
The concept of MRD-guided therapy—where treatment duration and intensity might be tailored based on MRD results—has gained significant momentum based on the MURANO findings. While not yet standard in clinical practice, ongoing research is exploring whether patients who achieve early uMRD might safely shorten their treatment duration, while those with persistent detectable MRD might benefit from extended therapy 4 .
The trial has also contributed to our understanding of resistance mechanisms. Interestingly, unlike some targeted therapies where specific mutations rapidly emerge to cause resistance, the MURANO analysis identified only three distinct BCL2 mutations in four patients, suggesting that resistance to fixed-duration VenR may develop through more diverse mechanisms 2 . This information is crucial for developing next-generation BCL-2 inhibitors and rational combination strategies.
Real-world evidence has further strengthened the MURANO findings, demonstrating that VenR remains effective and well-tolerated even in more diverse patient populations than those included in the original clinical trial 1 . As treatment paradigms continue to evolve, the MURANO trial represents a cornerstone achievement that has fundamentally changed how clinicians approach relapsed/refractory CLL, offering patients a finite treatment period with the potential for years of disease control and treatment-free remission.
The MURANO trial represents more than just another clinical study—it embodies a fundamental shift in how we approach cancer treatment. By demonstrating that a fixed-duration, chemotherapy-free regimen can produce long-lasting remissions even in relapsed/refractory CLL, it has challenged the paradigm of continuous therapy until progression that previously dominated oncology practice.
The implications extend beyond the immediate clinical benefits observed in the trial. The knowledge that patients can achieve years of treatment-free remission after a defined treatment period has profound quality-of-life implications, reducing both the physical burden of chronic medication and the psychological toll of endless treatment. Furthermore, the successful retreatment data provides both clinicians and patients with confidence that disease progression after VenR does not represent a therapeutic dead-end, but rather another chapter in the long-term management of this chronic disease.
As research continues to build upon the foundation established by MURANO—exploring novel combinations, MRD-guided approaches, and optimal sequencing strategies—the trial remains a landmark demonstration that sometimes, when fighting cancer, less can indeed be more.