Ibrutinib Plus Venetoclax Achieves MRD Undetectability in Patients with CLL

Constantine S. Tam, MD

Constantine S. Tam, MD

Undetectable minimal residual disease (uMRD) rates of 75% in the peripheral blood and 72% in the bone marrow were observed with the frontline combination of venetoclax (Venclexta) and ibrutinib (Imbruvica), in acohort of patients with chronic lymphocytic leukemia (CLL) evaluated in the phase II CAPTIVATE trial, according to data presented at the 2019 American Society of Hematology (ASH) Annual Meeting.

In the 11 patients who were given 12 cycles of ibrutinib/venetoclax, there was a 36% complete remission rate and a 36% partial response (PR) rate. There was also a 9% rate of nodular partial remissions (NPRs). Additionally, 60% of patients who had PRs or NPRs were MRD-negative.

Treatment with the combination regimen followed 3 cycles of ibrutinib lead-in. Investigators found that lead-in therapy reduced the risk of hospitalization for tumor lysis syndrome (TLS) by 76% in the study subjects, allowing them to continue on the study treatment for the full 15-month duration. Constantine S. Tam, MD, who presented the data at ASH, explained the implications of the results from the CAPTIVATE trial.

“These data mean that we now have an oral regimen that is chemotherapy-free, reliably achieves MRD clearance, and potentially allows these patients to have a limited 15-month duration of treatment. Then these patients can take a break from treatment,” Tam stated.

In an interview withTargeted Oncology, Tam, hematologist and disease group lead, Low Grade Lymphoma and Chronic Lymphocytic Leukemia and lead author of the phase II CAPTIVATE study, discussed the study findings in detail.

TARGETED ONCOLOGY: What was the rationale for the captivate trial?

Tam: The rationale for the CAPTIVATE trial was the fact that both ibrutinib and venetoclax are highly active in CLL, and the 2 drugs can be combined without overlap in toxicity. There is now a push to have targeted immunotherapy with novel agents. We tried combining ibrutinib and venetoclax to see if we could develop a regimen that is limited in duration and could limit MRD negativity.

The patients in the CAPTIVATE study received 3 months of treatment with ibrutinib to reduce the tumor lysis syndrome risk. Then they receive 12 months of ibrutinib plus venetoclax, after which they are tested for MRD.

The primary result of CAPTIVATE is that 75% of patients after 15 months on the novel therapy were MRD-negative in the blood, and 72% were negative in the bone marrow. These data mean that we now have an oral regimen that is chemotherapy-free, reliably achieves MRD clearance, and potentially allows these patients to have a limited 15-month duration of treatment. Then these patients can take a break from treatment.

TARGETED ONCOLOGY: What is the current understanding of MRD in CLL and how these data may contribute to them?

Tam: One of the important takeaway messages is that if you want your patient to have a long remission and good treatment-free survival, they should be MRD-negative at the time of treatment cessation. This is why a treatment like ibrutinib and venetoclax is so attractive in patients with CLL.

TARGETED ONCOLOGY: Can you discuss the safety profile of this combination?

Tam: Overall, the combination is well-tolerated. Five percent of patients had to stop the combination treatment due to adverse events (AEs), and overall, 90% of patients who started the treatment journey managed to complete the 15 months of treatment.

The major signals of toxicity were gastrointestinal. When you add venetoclax to ibrutinib, our experience has been that there is an increase in the incidence of diarrhea, nausea, and vomiting. All of these were grade 1 to 2 and were not treatment-limiting for patients. Also, because the treatment exposure is only 12 months, most patients can put up with these mild AEs for the improved treatment outcome.

There was also an increase in the incidence of neutropenia. Approximately one-third of patients had severe neutropenia, but less than 2% developed febrile neutropenia.

TARGETED ONCOLOGY: What are the next steps with this research?

Tam: The next steps would be for these patients who were treated in this study and in subsequent cohorts to have longer follow-up. We know that they're MRD-negative and that from the chemotherapy, they are likely to experience longer remission, but we need prolonged follow-up to confirm that the MRD-negative remissions are truly durable.

We also need to know which patients do not respond, how to deal with those patients, and improve their responses further.

TARGETED ONCOLOGY: What is the key takeaway from this research?

Tam: An important point to emphasize is that the 3 cycles of ibrutinib lead-in were effective in reducing the TLS risk of the patients. At baseline, 24% of patients were high TLS risk, but after 3 cycles of ibrutinib, that number was brought down to 2%, which meant that 3 cycles of ibrutinib lead-in took care of the TLS problems when we started venetoclax. Of 164 patients, only 1 patient got laboratory TLS, and there were no cases of clinical TLS.

Reference:

Tam CS, Siddiqi T, Allan JN, et al. Ibrutinib (ibr) plus venetoclax (ven) for first-line treatment of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL): results from the MRD cohort of the phase 2 CAPTIVATE study. Presented at: 2019 ASH Annual Meeting; December 7 to 10, 2019; Orlando, FL. Abstract 35.