Acalabrutinib and high-frequency low-dose subcutaneous rituximab for initial therapy of chronic lymphocytic leukemia.

Bruton tyrosine kinase inhibitors are an effective therapeutic agent for previously untreated patients with chronic lymphocytic leukemia but require indefinite treatment that can result in cumulative toxicities. Novel combinations of agents that provide deep remissions could allow for fixed duration therapy. Acalabrutinib, unlike ibrutinib, does not inhibit anti-CD20 monoclonal antibody-dependent cellular phagocytosis, making it a suitable partner drug to rituximab. Using standard dosing (375 mg/m2) of rituximab causes loss of target membrane CD20 cells and exhaustion of the finite cytotoxic capacity of the innate immune system. Alternatively, using high-frequency, low-dose (HFLD), subcutaneous rituximab limits loss of CD20 and allows for self-administration at home. The combination of HFLD rituximab 50 mg administered twice a week for 6 cycles of 28 days with the addition of acalabrutinib starting in week 2 was evaluated in a phase II study of 38 patients with treatment naive chronic lymphocytic leukemia. Patients achieving a complete response with undetectable minimal residual disease after 12 or 24 cycles of acalabrutinib could stop therapy. All patient responded, including one with a complete response with undetectable minimal residual disease in the peripheral blood and bone marrow at 12 months who stopped therapy. At a median follow-up of 2.3 years 2 patients with high-risk features have progressed while on acalabrutinib monotherapy. We conclude that HFLD rituximab in combination with acalabrutinib is an effective and tolerable self-administered home combination that provides a platform to build upon regimens that may more reliably allow for fixed-duration therapy. This trial was registered at www.clinicaltrials.gov #NCT03788291.