Ibrutinib Plus Venetoclax Leads to High Rates of MRD Negativity in Frontline CLL

The combination of ibrutinib with venetoclax – two agents that have been approved for the treatment of chronic lymphocytic leukemia (CLL) – led to high response rates and high rates of measurable residual disease (MRD) in patients who were newly diagnosed, according to findings reported in the New England Journal of Medicine. The safety profile of this all-oral combination was similar to what has been observed with either agent alone, the authors, led by Nitin Jain, MD, from the University of Texas MD Anderson Cancer Center, added.

The open-label, phase II study enrolled patients with CLL who were treated at MD Anderson between July 2016 and June 2018. All participants had at least one high-risk genetic feature, including del17p, mutated TP53, del11q, or unmutated IGHV. Patients older than 65 years also were eligible, independent of high-risk genetic features.

Per study protocol, patients received ibrutinib 420 mg once daily as a single agent for the first three cycles, to reduce the risk of venetoclax-associated tumor lysis syndrome (TLS), the investigators explained. At the start of cycle 4, participants received venetoclax, with a dose escalated weekly to a target of 400 mg once daily. Patients received ibrutinib and venetoclax for up to 24 cycles; if MRD was detectable at the end of treatment, ibrutinib alone could be continued until disease progression or unacceptable toxicity.

A total of 80 patients (median age = 65 years; range = 26-83 years) were included. Thirty percent were 70 years or older, and 83% had unmutated IGHV. Of the 80 patients, five withdrew from the study during the ibrutinib monotherapy phase and another six patients withdrew during the combination phase (2 with recurrent neutropenia, 1 with transformation to diffuse large B cell lymphoma, 1 with fallopian tube cancer, 1 with hemolytic anemia, and 1 who underwent allogeneic hematopoietic cell transplantation).

After the initial three cycles of ibrutinib, all remaining patients responded to treatment: one had a complete remission (CR) and 74 had partial remissions. After venetoclax was added, “the proportions of patients who had CR or CR with incomplete count recovery (CRi) with undetectable MRD in bone marrow increased over time,” the authors noted (TABLE 1).

During a median follow-up of 14.8 months (range not reported), three-quarters of patients experienced a CR/CRi as their best response. Notably, after six cycles of the ibrutinib-venetoclax combination, 28 of 70 evaluable patients (40%) were in remission and had undetectable MRD in their bone marrows. That percentage increased to 69% after 18 cycles of treatment (n=18/26).

This high response rate was observed across high-risk subgroups, the authors added, even in patients 65 years of age or older: After six cycles of combination treatment, 74% had CR/CRi and 44% had undetectable MRD (TABLE 2).

Three patients completed all 24 cycles of combined therapy – all of whom had CR or CRi and undetectable MRD.

The estimated one-year rates of progression-free and overall survival were 98% and 99%, respectively, and no patient has experienced CLL progression. However, the researchers noted, “Richter’s transformation developed in one patient, … a 63-year-old man with CLL with high-risk genomics.” One patient died, but the investigators found that this was unrelated to ibrutinib.

The investigators noted that “no new safety concerns were noted with combination therapy [and] the toxicity profile was similar to what has been noted for ibrutinib or venetoclax monotherapy.” Sixty percent of patients experienced a grade 3/4 adverse event (AE). The most common nonhematologic grade 3/4 AEs included atrial fibrillation (n=8; 10%) and hypertension (n=8; 10%); the most common hematologic grade 3/4 AE was neutropenia (48%). Neutropenia was managed by granulocyte colony stimulating factor and dose modifications of study drugs, the authors noted.

Three patients – two who were considered to be at medium risk for TLS and one at low risk for TLS, according to lymph node tumor burden on CT imaging and the absolute lymphocyte count – had laboratory evidence of TLS, while no patient had clinical evidence of TLS.

The findings from this analysis are limited by the lack of a comparator arm and the single-center design. Extended follow-up will provide more insights into targeted therapy in this patient population, the authors concluded. Remaining questions include whether treatment can safely be stopped or which subgroups with a poor prognosis may require additional therapy.

The authors report relationships with Janssen, AbbVie, and Genentech, the manufacturers of the study drug.


Jain N, Keating M, Thompson P, et al. Ibrutinib and venetoclax for first-line treatment of CLL. N Engl J Med. 2019;380:2095-103.