Promising Outcomes of Two-Year Pirtobrutinib with Venetoclax for Relapsed/Refractory CLL

For people with relapsed or refractory chronic lymphocytic leukemia (CLL), researchers are exploring whether taking pirtobrutinib (Jaypirca, Eli Lilly) and venetoclax (Venclexta, AbbVie) with or without rituximab (Rituxan, Genentech) for just two years can be an effective strategy. Learn more about this approach from a recent study below. 

Why Combine Pirtobrutinib and Venetoclax?

Many of the latest clinical trials have focused on combining BTK and BCL-2 inhibitors because these drug classes enhance each other’s effectiveness. Unlike traditional covalent BTK inhibitors (cBTKi, like acalabrutinib), pirtobrutinib—a non-covalent BTK inhibitor—can overcome the resistance that develops with long-term cBTKi use. 

While pirtobrutinib is currently FDA-approved as a continuous-duration treatment, evaluating its combination with venetoclax for a fixed duration is a new approach. A key limitation of pirtobrutinib alone is that its effectiveness typically wanes within two years, depending on prior treatments. However, pairing it with venetoclax for a set period may enhance its efficacy. 

Pirtobrutinib and Venetoclax Phase 1 Outcomes 

In a phase 1 study, 25 adults with relapsed/refractory CLL received either a combination of pirtobrutinib and venetoclax (PV) or pirtobrutinib, venetoclax, and rituximab (PVR) for a fixed duration of 25 cycles (approximately two years).

Achieving Remission

Among all patients treated with PV or PVR, 96% experienced a reduction in cancer cells following treatment, reflecting the overall response rate. Notably, 40% of these individuals achieved a complete response, meaning they had normal blood levels and no enlarged spleen or lymph nodes. 

18 months after achieving a response, 93% of patients in the PV group and 80% of patients in the PVR group were still in remission (duration of response).

Minimal Residual Disease (MRD) Testing

The researchers also assessed minimal residual disease (MRD), a highly sensitive test that detects remaining cancer cells. Achieving undetectable minimal residual disease (uMRD) is significant because it predicts a longer duration of remission.

In this study, the sensitivity threshold was uMRD4, indicating fewer than 1 CLL cell per 10,000 white blood cells in a blood sample, as measured by clonoSEQ. Among both PV and PVR groups, results showed:

• 70.8% of patients achieved uMRD4 after 12 months
• 87.5% reached uMRD4 at some point during the trial

These early findings are promising, suggesting that pirtobrutinib and venetoclax, with or without rituximab, can induce deep responses. This is particularly noteworthy given that 68% of patients had previously been treated with covalent BTK inhibitors (cBTKis), the majority of whom had developed resistance.

Side Effects

While common side effects such as low white blood cells, diarrhea, fatigue, and nausea occurred, they were manageable—98% of patients were able to complete the full course of treatment. Additionally, researchers found no drug interactions between pirtobrutinib and venetoclax, confirming their safety when taken together.

Overall, these findings highlight the promising potential of pirtobrutinib and venetoclax, with or without rituximab, for patients with relapsed/refractory CLL, including those previously treated with a covalent BTK inhibitor. 

Limitations and Future Research

While the study results are encouraging, the small number of patients makes it harder to compare different treatment options. More research is needed to see if the benefits last over time and whether some patients might do better with a shorter or longer treatment plan.

A larger phase 3 trial is now in progress to test this treatment in more patients. Researchers are also studying other combinations with pirtobrutinib, not just for patients whose CLL has returned or stopped responding to treatment but also for those receiving treatment for the first time. Examples include: 

• First-Time Treated CLL? Learn About a New Combination of Pirtobrutinib + Obinutuzumab
• Pirtobrutinib and Venetoclax with MRD Detection for Previously Untreated Chronic Lymphocytic Leukemia
• Time-limited Triplet Combination of Pirtobrutinib, Venetoclax, and Obinutuzumab for Patients With Treatment-naïve Chronic Lymphocytic Leukemia (CLL) or Richter Transformation (RT) 

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Source: 

• Fixed-duration pirtobrutinib plus venetoclax with or without rituximab in relapsed/refractory CLL: the phase 1b BRUIN trial