Ibrutinib plus Venetoclax Combo Elicits Impressive Responses in Relapsed Chronic Lymphocytic LeukemiaLeukemia, Web Exclusives
Atlanta, GA—Ibrutinib (Imbruvica) plus venetoclax (Venclexta) led to an objective response rate of 100% in patients with relapsed or refractory chronic lymphocytic leukemia (CLL), with 47% in complete remission at 6 months. These high response rates were achieved with only 1 case of laboratory tumor lysis syndrome, said Peter Hillmen, MBChB, PhD, FRCP, FRCPath, Leader, Section of Experimental Haematology, Leeds Institute of Cancer and Pathology, United Kingdom, at ASH 2017.
Data from the CLARITY clinical trial showed that approximately 33% of 38 patients evaluable for efficacy had minimal residual disease (MRD) in their bone marrow 6 months after receiving this combination.
Ibrutinib improves overall survival and progression-free survival in patients with relapsed or treatment-naïve CLL, “However, ibrutinib does not eradicate residual disease as a single agent in many patients,” said Dr Hillmen.
Venetoclax also elicits good responses in patients with CLL, leading to rare instances of tumor lysis syndrome that necessitate a slow dose increase in the first month. “However, this tumor lysis does translate into the eradication of detectable disease in a small proportion of patients,” Dr Hillmen told attendees.
These observations led to the design of the CLARITY study, in which 54 patients with relapsed or refractory CLL were enrolled; of these, 50 patients received the daily combination of ibrutinib 420 mg plus venetoclax 400 mg. Patients received 8 weeks of ibrutinib monotherapy followed by the addition of weekly venetoclax escalation therapy, starting at 20 mg, until the full 400-mg dose.
Treatment was stopped at 14 months if the 8-month bone marrow assessment was negative for MRD. Treatment was stopped at 26 months if the 14-month bone marrow assessment was MRD-negative. Ibrutinib alone was continued if the bone marrow was MRD-positive at 26 months. MRD was defined as <0.01% CLL cells in the bone marrow. In all, 4 patients stopped taking ibrutinib before adding venetoclax because of toxicity; 49 patients successfully passed through venetoclax escalation.
Overall, 8% of the patients had bulky disease (defined as lymph nodes ≥5 cm); 20% had 17p deletions; and 25% had 11q deletions without 17p deletions.
The median number of previous therapies was 1, with a maximum of 6. The most common previous therapies were fludarabine, cyclophosphamide, and rituximab (FCR) or bendamustine and rituximab (BR) in 81% of patients. Approximately 44% of patients had relapsed within 3 years of receiving BR or FCR. Twenty percent of patients had previously received idelalisib (Zydelig).
“The vast majority of adverse events were grade 1 and did not lead to stopping the treatment,” said Dr Hillmen. The most common adverse event of interest was bruising, in 33 patients. Of 25 cases of neutropenia, 6 were grade 3 and 6 were grade 4. The 1 patient who had tumor lysis syndrome was managed by delaying venetoclax, which was rapidly re-escalated with no further tumor lysis syndrome.
All 38 patients who were evaluable for efficacy experienced at least a partial response. There were 15 (38%) patients with a complete response, and 3 (8%) with a complete response with incomplete hematologic recovery. At 8 months, 15 (37%) patients were negative for MRD in the peripheral blood, and 12 (32%) patients were MRD negative in the bone marrow. The remainder (53%) of the patients had a partial response. Among the patients who relapsed with FCR or BR treatment in <36 months, the MRD rates in the peripheral blood and bone marrow were 52% and 41%, respectively.
A phase 3 clinical trial of ibrutinib plus venetoclax combination as first line for CLL is currently enrolling patients.
Laurie Sehn, MD, MPH, Medical Oncologist, British Columbia Cancer Agency, Vancouver, Canada, said that the results of CLARITY were impressive and herald “an era where we can use these targeted therapies to replace some of the toxic agents used to treat hematological disorders.”
Reprogramming patients’ immune cells to treat their cancer has become the front line of cancer therapy, with chimeric antigen receptor (CAR) T-cell therapy now approved by the FDA for several blood cancers. But translating this success to solid tumors remains a challenge. At the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting, Gianpietro Dotti, MD, Cancer Cellular Immunotherapy Program, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, discussed efforts to extend the application of CAR T-cell therapy to solid tumors.
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