Loncastuximab Tesirine in Combination with Venetoclax Is Safe and Shows Efficacy in Patients with Relapsed/Refractory Non Hodgkin Lymphoma

Background: Loncastuximab tesirine (lonca) is active in patients with refractory or relapsed (r/r) aggressive B cell non-Hodgkin lymphoma (B-NHL) and is approved after 2 or more lines of therapy. The combination of lonca with venetoclax (VEN) has been shown to have synergistic activity against lymphoma models in vitro and in vivo (Tarantelli C, et al. Haematologica 2024). We present the full dose escalation data of a single - center phase I trial evaluating the safety, tolerability and efficacy of lonca + VEN combination therapy.

Methods: Eligible patients included adults diagnosed with B-NHL that was r/r after at 2 or more prior systemic therapies. Lonca was administered on day 1 and VEN on days 1 – 5 of each 21-day cycle. Patients received VEN ramp-up dosing during cycle 1 (20-50-100-200-400mg) and 400mg daily on subsequent cycles. A maximum of 6 cycles was administered. Lonca dose escalation was done using BOIN design and three dose levels were tested: 50, 100 and 150 mcg/kg, with patients in the two latter dose levels receiving 50 mcg/kg and 75 mcg/kg on cycles 3 onwards, respectively. Response rates were assessed using Lugano criteria (Cheson et al. J Clin Oncol 2014)

Results: Thirteen patients enrolled and received at least one cycle of study treatment, including 8 patients with diffuse large B cell lymphoma (DLBCL), 3 patients with follicular lymphoma and 2 patients with Waldenstrom macroglobulinemia. Patients had a median age of 66 years (range 48-84), 4 (31%) were women, all were white and 3 (25%) had ECOG performance of 0. The median number of prior lines of therapy was 4 (range 3-9) and 12 (92%) patients were refractory to the last line of therapy. Eight (62%) had prior anti-CD19 CAR T cell therapy. We observed one dose limiting toxicity (DLT) at dose level 2 (grade 3 atrial fibrillation with rapid ventricular rate). No additional DLTs were observed. Five patients were treated on DL1, 5 on DL 2 and 3 on DL3. Enrollment continues in dose expansion at DL3.

All patients treated were evaluable for toxicity. The most common adverse events (AE) were anemia (n = 8, 67%), leukopenia (n = 7, 58%), thrombocytopenia (n = 6, 50%), and hyponatremia (n = 5). Skin abnormalities were observed in 6 (50%) patients including 3 (25%) cases of maculopapular rash; generalized edema or extremity edema occurred 5 (42%) patients and elevated gamma glutamyl transferase was observed in 4 (33%) patients. The most common grade 3 or higher AEs included neutropenia in 4 patients and atrial fibrillation, hypotension, generalized muscle weakness and increase bilirubin in 2 cases each. Two patients died while receiving active trial interventions: one case of pulmonary aspergillosis after COVID 19 pneumonia and one case of acute renal failure, malabsorption, and ascites in the context of intestinal involvement by DLBCL.

Among 11 efficacy – evaluable patients, 7 patients responded and 5 achieved CR, with overall and complete response rates of 64% and 45%, respectively. Among 4 aggressive NHL patients who had prior CAR T cell therapy, 3 responded to lonca + ven.

Conclusions: This is the first prospective clinical trial showing that the addition of venetoclax to loncastuximab is safe and efficacious in r/r B-NHL, including DLBCL patients whose disease progressed after anti-CD19 CAR T cells. Both patients with heavily treated refractory Waldenstrom macroglobulinemia achieved complete remission after this treatment. Enrollment continues in a dose expansion cohort that also includes patients with r/r mantle cell lymphoma. Updated analyses with longer follow-up and expanded enrollment will be presented.