High-Frequency Low-Dose Acalabrutinib/Rituximab Combo Elicits 100% ORR in Frontline CLL/SLL

High-frequency low-dose acalabrutinib (Calquence) and rituximab (Rituxan) represents a feasible and effective combination for the treatment of patients with previously untreated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL), according to results from a phase 2 study that was presented during the 2021 ASH Annual Meeting.¹

All 37 patients enrolled responded to the combination; however, 1 patient had a complete response but with peripheral blood testing positive for minimal residual disease (MRD), said lead study author Danielle S. Wallace, MD, in a presentation during the meeting.

In addition, she said the regimen has advantages that could prove useful during the COVID-19 pandemic.

“This at-home combination decreased infusion time and patient interactions during the pandemic,” said Wallace, a second-year fellow at Wilmot Cancer Institute, University of Rochester Medical Center. “This regimen has the potential to enable rituximab to be administered at facilities with limited medical intravenous infusion capacity, which could be very useful in rural and economically disadvantaged areas.”

At a median follow-up of 14.0 months, 27 patients (73%) have completed at least 12 cycles of therapy. In addition to the 1 patient (2.7%) with a CR but peripheral blood tested that positive, there were 20 partial responses (PR; 54%) and 6 PRs with sustained lymphocytosis (16%). “To date, 10 patients have completed 24 cycles, and all were in sustained PRs at the time of their response assessment,” she said. One patient with both a del(17p) and TP53 mutation has had progressive disease following 25 cycles of therapy.

CD20 antibodies such as rituximab primarily destroy B cells by activating the innate immune system. Standard intermittent dose rituximab may be less effective in CLL than intermittent high frequency low dose because “higher doses result in rapid exhaustion of the finite mechanisms of the innate immune system, via a reduction in phagocytosis and loss of CD20 expression due to trogocytosis,” said Wallace.

In earlier lines, in which rituximab was given 2 to 3 times a week at lower doses of 20 mg/m2, loss of CD20 was not significant,2 she said, “supporting further trials of high frequency low-dose rituximab.” The subcutaneous dosing of rituximab that is approved in CLL is more convenient and preferable to patients, allowing the drug to be administered in the patient’s home.

In the single-center, single-arm phase 2 study, 37 patients with CLL/SLL who were not previously treated, who required treatment based on International Workshop on CLL criteria, received rituximab at 50 mg IV on day 1 of cycle 1, followed by 50 mg subcutaneously dosing twice a week for 6 cycles. Acalabrutinib, 100 mg twice daily, was started on day 8 of cycle 1. After 6 cycles, each lasting 28 days, acalabrutinib was administered alone. Following 12 cycle, response was assessed. If MRD testing in the peripheral blood was negative, patients underwent a bone marrow biopsy to confirm CR. If a patient was MRD negative, therapy was stopped and the patient was followed until disease progression. Another repeat response assessment was performed at 24 cycles.

The median age of patients was 67 years (range, 39.8-78.0), and 60% were male. Patients enrolled were relatively high risk, she said, with 70.2% having at least 1 high-risk feature, including 21.6% with a TP53 mutation and 13.5% with del(17p).

“While all patients have responded to therapy, no patients to date have achieved an undetectable MRD-CR, suggesting that additional agents are required to allow for time-limited therapy,” Wallace said.

Regarding safety, grade 3/4 adverse events (AEs) occurring in at least 5% of patients were infections (13.5%), neutropenia (8.1%) and anemia (8.1%). The most common all-grade and all-causality AEs were infusion-related reactions (62.1%), infections (56.8%), fatigue (51.3%), anemia (51.3%), headache (43.2%), rash or other skin changes (32.4%), thrombocytopenia (29.7%), upper respiratory infections (29.7%), urinary tract infections (18.9%), COVID-19 pneumonia (8.1%), bruising (27.0%), and diarrhea (21.6%). None of the patients who contracted COVID-19 pneumonia required intubation and all remained on acalabrutinib during their infection.

All infusion reactions occurred during the second hour of infusion, and none required discontinuation of rituximab. Subsequently, only 3 patients had injection site reactions with subcutaneous dosing. There were 11 serious adverse events, the majority of which were infections. No deaths occurred on treatment.

Reference

1. Wallace DS, Baran AM, Friedberg JW, et al. 2640 Phase II study of acalabrutinib and high-frequency low-dose subcutaneous rituximab in patients with previously untreated chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Presented at: 2021 ASH Annual Meeting and Exposition; December 11-14, 2021; Atlanta, GA. Abstract 2640.
2. Zent CS, Taylor RP, Lindorfer MA, et al. Chemoimmunotherapy for relapsed/refractory and progressive 17p13-deleted chronic lymphocytic leukemia (CLL) combining pentostatin, alemtuzumab, and low-dose rituximab is effective and tolerable and limits loss of CD20 expression by circulating CLL cells. Am J Hematol. 2014;89(7):757-765. doi:10.1002/ajh.23737