Ibrutinib combinations in CLL therapy: scientific rationale and clinical results

Abstract

Ibrutinib has revolutionized the treatment of chronic lymphocytic leukemia (CLL). This drug irreversibly inhibits Bruton tyrosine kinase (BTK) by covalently binding to the C481 residue in the BTK kinase domain. BTK is a pivotal protein for B cell receptor signaling and tissue homing of CLL cells. Preclinical investigations have established the importance of the B cell receptor pathway in the maintenance and survival of normal and malignant B cells, underscoring the importance of targeting this axis for CLL. Clinical trials demonstrated overall and progression-free survival benefit with ibrutinib in multiple CLL subgroups, including patients with relapsed or refractory disease, patients with 17p deletion, elderly patients, and treatment-naïve patients. Consequently, ibrutinib was approved by the US Food and Drug Administration for newly diagnosed and relapsed disease. Ibrutinib has transformed the treatment of CLL; however, several limitations have been identified, including low complete remission rates, development of resistance, and uncommon substantial toxicities. Further, ibrutinib must be used until disease progression, which imposes a financial burden on patients and society. These limitations were the impetus for the development of ibrutinib combinations. Four strategies have been tested in recent years: combinations of ibrutinib with immunotherapy, chemoimmunotherapy, cell therapy, and other targeted therapy. Here, we review the scientific rationale for and clinical outcome of each strategy. Among these strategies, ibrutinib with targeted agent venetoclax results in high complete response rates and, importantly, high rates of undetectable minimal residual disease. Although we concentrate here on ibrutinib, similar combinations are expected or ongoing with acalabrutinib, tirabrutinib, and zanubrutinib, second-generation BTK inhibitors. Future investigations will focus on the feasibility of discontinuing ibrutinib combinations after a defined time; the therapeutic benefit of adding a third agent to ibrutinib-containing combinations; and profiling of resistant clones that develop after combination treatment. A new standard of care for CLL is expected to emerge from these investigations.

Fig. 1. Rationale for ibrutinib combination with monoclonal antibodies.

Ibrutinib (IBR) reduces levels of smCXCR4, leading to enhanced CLL cell egress from the lymph nodes and spleen to the circulation and impaired homing to the nodal compartments. In peripheral blood, CLL cells are exposed to monoclonal antibodies by three major independent mechanisms: (1) antibody-dependent cellular cytotoxicity (ADCC), (2) complement-mediated cytotoxicity, and (3) direct apoptosis. This figure was created with BioRender.com. BCR, B cell receptor.

Fig. 2. Rationale for ibrutinib combination with chemoimmunotherapy.

Ibrutinib (IBR) leads to CLL cell mobilization from the nodal compartment, making CLL cells more accessible to chemotherapy and anti-CD20 antibody in peripheral blood. Lower left diagram depicts intracellular mechanism of combination. Anti-CD20 antibody along with chemotherapy induces apoptosis and immunologic cell death, while ibrutinib affects proliferation, survival, and migration of B cells. Chemotherapeutic agents such as fludarabine are well known to cause depletion of all T cell subsets, thereby reducing negative trophic signals between T cells and CLL cells. This figure was created with BioRender.com. BCR, B cell receptor.

Fig. 3. Rationale for ibrutinib combination with cell therapy.

Unlike several commonly used treatments (chemotherapy, alemtuzumab), ibrutinib (IBR) does not have a profound negative impact on T cell function. Due to off-target effect of ibrutinib on ITK, there is a shift towards cellular immunity (Th1 ↑, Th2 ↓). Ibrutinib therapy for five to 11 cycles before T cell separation leads to an increased CAR-T cell proliferation rate. The mobilizing effect of ibrutinib may make CLL cells more accessible to CAR-T cells. This figure was created with BioRender.com.

Fig. 4. Rationale for ibrutinib combination with targeted agent venetoclax.

Ibrutinib (IBR) results in mobilization of CLL cells from protective microenvironment niches in lymph nodes, while venetoclax hits CLL cells residing in the blood and bone marrow. Venetoclax targets BCL-2 to induce apoptosis, but MCL-1 could protect malignant cells from mitochondria-mediated cell death. IBR treatment results in a decrease in MCL-1 protein level and leads to synergy when combined with venetoclax. This figure was created with BioRender.com.