Chronic lymphocytic leukemia (CLL), or its variant small lymphocytic lymphoma (SLL), is the most common type of leukemia, a cancer in the blood and bone marrow. In patients with CLL or SLL who have not received previous therapy, including patients with high-risk disease, the use of the Bruton tyrosine kinase (BTK) inhibitor Imbruvica (ibrutinib) plus the BCL inhibitor Venclexta (venetoclax) resulted in deep remissions, according to new results from a phase 2 clinical trial, the CAPTIVATE MRD study.
Photo © ASCO/Scott Morgan 2018
The results were presented at the 2020 annual meeting of the European Hematology Association by the lead study investigator, Tanya Siddiqi, MD, Hematologist/Oncologist with the City of Hope Comprehensive Cancer Center, Duarte, California.
Imbruvica and Venclexta are each approved by the FDA for the treatment of patients with CLL or SLL. Imbruvica is also approved for the treatment of patients with high-risk CLL and deletion 17p, a rare genomic aberration in CLL.
The approval in the last decade of several drugs that target the B-cell antigen receptor, including BTK inhibitors and BCL inhibitors, has dramatically changed the approach to therapy for patients with CLL.
Studies have shown that the B-cell receptor is a crucial feature in the development of CLL. Therefore, drugs that target these malignant B-cells, including BTK and BCL inhibitors, are beneficial for the treatment of patients with CLL.
Undetectable Disease
In the CAPTIVATE MRD study, investigators used the BTK inhibitor Imbruvica with the BCL inhibitor Venclexta to see if the combination of these 2 targeted therapies can improve the response to therapy in patients with CLL compared with each drug alone.
According to Dr. Siddiqi, the CAPTIVATE MRD “phase 2 study supports synergistic antitumor activity of the combination with notable deep responses,” meaning that these 2 drugs work together to produce good or deep responses to treatment in patients with different risk levels of CLL or SLL.
The study included patients with high-risk CLL, including 16% of patients with deletion 17p, 19% with complex karyotype, and 59% of the patients without the IGHV mutation (a genomic alteration that improves survival in CLL).
To determine the response to therapy, the researchers used the measure of negative or undetectable minimal residual disease (or MRD). This means that the patient does not have any sign of cancer in the blood or bone marrow.
Dr. Siddiqi and her colleagues studied the benefit of using the 2 drugs together to fight CLL, by measuring the duration and the depth of MRD response. The results presented at the meeting were collected before the patients were divided into the study groups; the findings were evaluated using earlier data of patients who had only minimal sign of disease after receiving 12 cycles of this combination.
The investigators analyzed the results for the intention-to-treat population of 164 patients with CLL or SLL who received treatment with Imbruvica plus Venclexta. After receiving Imbruvica once daily for 3 cycles of 28 days each, Venclexta was added to the daily therapy for an additional 12 cycles, for a total of 15 cycles of therapy.
Among the patients who received up to 12 cycles of this combination therapy, the proportion of patients with undetectable residual disease in the blood increased over time, from 57% after 6 cycles of therapy to 75% after 12 cycles, Dr. Siddiqi said. In addition, 68% of patients had undetectable MRD in the bone marrow, meaning they had no detectable sign of cancer in the blood or in the bone marrow.
High MRD Rates
The overall response to therapy rate after 12 cycles was 97%, including 51% of patients who had a complete response (no sign of cancer) or complete response with incomplete bone marrow recovery, and 46% of patients who had a partial response or a nodular partial response.
Among the patients with a complete response or complete response with incomplete bone marrow recovery, 85% had undetectable MRD in the blood and 80% had undetectable MRD in the bone marrow. In the patients with a partial response or nodular partial response, 69% had undetectable MRD in the blood and 59% had undetectable MRD in the bone marrow.
The high rates of undetectable MRD were seen among all patients in the study, regardless of their characteristics, such as deletion 17p, bulky disease, cytogenetic risk category, TP53 mutation, or complex karyotype.
After 15 cycles of therapy, the patients were evaluated for the risk of tumor lysis syndrome (a serious side effect of cancer or cancer treatment), MRD status, and other signs of response to therapy.
A majority of the patients had reductions in lymph node burden after the 3-cycle ibrutinib lead in. The risk for tumor lysis syndrome also decreased during the initial treatment with Imbruvica: 90% of patients who had a high risk of tumor lysis syndrome at the start of treatment changed to low- or medium-risk level, with no patients moving to the high-risk category.
“Hospitalization because of this was no longer required in 66% of at-risk patients after 3 cycles of ibrutinib lead in, and 82% of patients initiated venetoclax ramp up without the need for hospitalization,” Dr. Siddiqi said.
Expert Commentary
Catherine C. Coombs, MD, of the University of North Carolina Lineberger Cancer Center, at Chapel Hill, North Carolina, commented on the study results. She said that the results are promising, but it is not clear if it is better to use Imbruvica and Venclexta together from the start or in sequence.
Dr. Coombs also said that it is not clear if this is the best combination available, or if Venclexta plus Gazyva (obinutuzumab), a CD20-directed monoclonal antibody, which has also shown high rates of negative MRD when used as first-line therapy, would be better. She suggested that using this combination first would allow doctors to use Imbruvica or the newer BTK inhibitor Calquence (acalabrutinib) in patients whose disease relapses (returns).
“I think this is promising, but the informative and practice-changing study would be to compare this combination to ibrutinib monotherapy or to venetoclax and obinutuzumab,” which is now being examined in another study, Dr. Coombs said.
Side Effects
The most common side effects with Imbruvica plus Venclexta were diarrhea, joint pain, fatigue, headache, and nausea. Serious side effects included grade 3 neutropenia in 17% of patients and grade 4 neutropenia in 16%. Grade 3 febrile neutropenia and tumor lysis syndrome occurred in 2 (1%) patients each.
Overall, 8 patients stopped treatment because of side effects, but no deaths were reported because of therapy with Imbruvica plus Venclexta itself.
