CLL Research: Triple-Combination IVO (Ibrutinib + Venetoclax + Obinutuzumab)
During the 62nd Annual Meeting and Exposition of the American Society of Hematology (ASH2020), Dr. Kerry A Rogers, M.D., a Chronic Lymphocytic Leukemia (CLL) specialist at the James Cancer Center of the Ohio State University, in Columbus, OH, gave an oral poster presentation entitled: Three-Year Follow-up from a Phase 2 Study of Combination Obinutuzumab, Ibrutinib and Venetoclax in Chronic Lymphocytic Leukemia.
Background – Triple-Combination IVO
The development of targeted therapies has led to highly effective treatments that avoid traditional cytotoxic chemotherapy. Conventional chemotherapy agents are highly potent chemicals that kill rapidly dividing cells. As most cancers are fast-growing, they have been successfully used to treat cancer for decades. Unfortunately, cytotoxic chemotherapy agents lack the ability only to target the cancer cell. Many of the side effects of chemotherapy, such as hair loss, mouth ulcers, and skin breakdowns result from this indiscriminate assault on healthy and malignant cells.
Recent advances in understanding cancer cell biochemistry have led to the knowledge that specific proteins are over-expressed in malignant cells compared to healthy cells. Further, we have gained insight into the roles these proteins play in cell growth (proliferation) and cell death (apoptosis).
The triple-combination IVO takes advantage of three specific targets. Ibrutinib (Imbruvica®) blocks the Bruton’s Tyrosine Kinase(BTK) protein that is over-expressed on the surface of CLL cells. BTK is known to reduce the rapid growth of CLL cells, known as “cell proliferation.” As a single agent, ibrutinib produces few complete responses (CR). Still, it has a demonstrated
history of stabilizing CLL to the point where most patients no longer have symptoms, and blood counts trend toward normal levels over time. Venetoclax (Venclexta®) targets the B-cell Lymphoma 2 (BCL2) protein. BCL2 on the CLL cell inhibits the normal cell death process, known as apoptosis. By blocking, BCL2 results in this stopping this inhibition of apoptosis, and rapid cell death occurs. Cell death can be so profound that initial therapy uses a 5-step dose-escalation titration. This quick cell death has resulted in Tumor Lysis Syndrome cases, which can be life-threatening and needs monitoring and prevention strategies to reduce harm. Venetoclax monotherapy has a higher CR than ibrutinib, and continuous therapy, similar to ibrutinib, is recommended. Obinutuzumab (Gazyva®) is an Anti-CD 20 monoclonal antibody. CD20 appears to play a role in B-cell development, differentiation, B-cell receptor (BCR) signaling, and cell-cycle initiation events.
Combination therapies have more significant toxicities than monotherapy. Combinations of ibrutinib plus venetoclax or venetoclax plus either of the two Anti-CD20 antibodies (rituximab and obinutuzumab) have excellent response rates. They frequently lead to the achievement of undetectable Measurable Residual Disease (uMRD) and are used for fixed durations.
Methods - OSU Phase II Study of Triple-Combination IVO
The Ohio State University (OSO) sponsored this Phase 2 Trial that included separate cohorts to treatment-naïve (TN) and relapsed or refractory (RR) CLL patients. Treatment with triple- combination IVO was for 14 cycles of 28-days each. For the first cycle, patients received only obinutuzumab. Ibrutinib started at the beginning of cycle-2. The venetoclax dose ramp up commenced on day 1 of cycle-3, with the full dose (400mg) reached by the start of cycle-4.
Patient responses to treatment were measure using the iwCLL (International Workshop on CLL) 2008 criteria at two months after completing cycle-14. Bone Marrow and peripheral blood samples were analyzed to determine MRD status using standard ten-color flow cytometry with a cutoff of less than one cell in 10,000 at the end of treatment. Patients’ follow-ups occurred every three months for the first two years after the end of therapy and then shifted to six-month intervals. Patient evaluations continue unless they started another treatment, they experience disease progression, or die.
Progression-free survival (PFS) and overall survival were estimated using the Kaplan-Meyer method.
The diagram to the right (below on mobile) shows characteristics of the two cohorts of patients in this phase 2 trial using combination obinutuzumab, ibrutinib and venetoclax, and includes information on age, gender, number of prior treatments, and risk factors.
Results: Three-Year Follow-up of Phase 2 Study of Triple-Combination IVO
Enrollment ended in April 2017, and the cutoff for data for this report was July 6, 2020. Forty-three patients completed the planned treatment of 14-cycles. Seven patients did not complete treatment. Of the seven who did not finish treatment, three each were for adverse events or patient/physician preference. One patient was diagnosed with concomitant chronic myeloid leukemia (CML).
Seven patients (28%) in each group achieved uMRD accompanied by a complete response (CR). CR is defined as all hematologic lab values are in the normal range, and there is no lymph node or organ enlargement.
Fourteen (14) [56%] TN patients treated with triple-combination IVO achieved undetectable MRD (uMRD) in the blood and bone marrow.
Similarly, eleven (11) [44%] of RR patients reached uMRD.
Conclusions: Promising Results from Triple-Combination IVO
The combination of fixed-duration ibrutinib, venetoclax, and obinutuzumab led to high overall response and undetectable measurable or minimal residual disease rates. These responses remain durable at three years.