Efficacy and safety of loncastuximab tesirine and rituximab (Lonca-R) followed by dose-adjusted rituximab with etoposide, doxorubicin, cyclophosphamide, vincristine and prednisone (DA-R-EPOCH) in previously untreated high-risk diffuse large B-cell ly

Abstract Background: Newly diagnosed DLBCL is a potentially curable malignancy. However, there are high-risk subsets that respond poorly to and have worse outcomes using standard first-line immunochemotherapy with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Double-expressor/double-hit DLBCL (DEL/DHL) is one such subset. Both loncastuximab tesirine and DA-R-EPOCH have previously demonstrated efficacy in this subgroup. We evaluated the safety and efficacy of Lonca-R followed by DA-R-EPOCH in previously untreated patients with DEL/DHL. Methods: Patients aged ≥18 years with histologically or cytologically confirmed untreated DEL and DHL per 2016 World Health Organization (WHO) criteria (DEL: MYC >40% and BCL2 >50% by immunohistochemistry; DHL: rearrangements in MYC and BCL2 and/or BCL6 by fluorescent in-situ hybridization) with an Eastern Cooperative Oncology Group (ECOG) score ≤ 2 were enrolled in this prospective single-arm phase II trial within the UCHMC. A “smart start approach” was used to administer 2 three-week cycles of Lonca-R: rituximab 375 mg/m2 intravenously (IV) given on cycle 1, day 1 followed by loncastuximab tesirine 150 μg/kg IV on cycle 1, day 7. On day 1 of cycle 2, both rituximab 375 mg/m2 IV and loncastuximab tesirine 150 μg/kg IV were administered concurrently. After completing 2 cycles of Lonca-R, patients were assessed for response and received up to 6 cycles of DA-R-EPOCH starting at the level 1 dose with rituximab 375 mg/m^2 IV on day 1, etoposide 50 mg/m2/day continuous intravenous infusion (CIVI) on days 1-4 (D1-4) doxorubicin 10 mg/m2/day CIVI D1-4, cyclophosphamide 750 mg/m2 on day 5, vincristine 0.4 mg/m2/day CIVI D1-4, and prednisone 60 mg/m2 twice daily on days 1-5. Subsequent cycles of DA-R-EPOCH were escalated/de-escalated per standard protocol. Patients discontinued therapy at completion of 6 cycles of DA-R-EPOCH, progressive disease, unacceptable toxicity, withdrawal of consent, treatment non-adherence, or administrative reasons. Computed tomography (CT) of the chest/abdomen/pelvis and positron emission tomography/CT were obtained at baseline, every 2 cycles during treatment, and at the end of treatment to assess response using the 2014 Lugano classification. Toxicity was assessed each cycle as per the CTCAEv5.0. Kaplan-Meier curves were used to calculate progression-free survival (PFS) and overall survival (OS). Results: Ten patients have been enrolled; however, only 9 had data available for analysis. 89% (8/9) were male and the median age was 66 years (range, 30-75 years). 67% (6/9) of patients had DEL, 11% (1/9) had DHL, and 22% (2/9) had DHL and DEL. 56% (5/9) had an International Prognostic Index of ≥ 3. All patients had an ECOG of 0-1. 44% (4/9) patients had only nodal disease, 22% (2/9) had only extranodal disease, and 33% (3/9) had both nodal and extranodal disease at the time of diagnosis. 78% (7/9) of patients completed all 8 cycles, with 1 patient stopping study treatment due to disease progression after cycle 1 and the other stopping after cycle 4 as he moved from the area. Overall response rate (ORR) after 2 cycles was 88% (7/8); 1 patient had stable disease (SD) and 1 achieved complete response (CR). ORR after 8 cycles was 100% (7/7); 71% (5/7) achieved and continue to remain in CR. Estimated 1 and 2-year rates of PFS, respectively, were 76.2% (95% confidence interval [CI], 52.1-100.0%) and 57.1% (95% CI, 28.9-100%). Estimated 1 and 2-year rates of OS, respectively, were 100% (95% CI, 100-100%) and 75% (95% CI, 42.6-100%). Median PFS and OS were not reached. 89% of possible or probable patient-reported, treatment-related adverse effects (AEs) were either grade 1 (G1) or grade 2 (G2). The most common G1 and G2 AEs were hyperglycemia, peripheral sensory neuropathy, and maculopapular rash. There were 20 possible or probable reported grade 3 (G3) or 4 (G4) AEs. The most common G3 and G4 AEs were decreased neutrophil count, febrile neutropenia, and anemia. Conclusion: Lonca-R followed by DA-R-EPOCH appears to be a promising regimen for patients with DHL and/or DEL. ORR was >80% in patients who had completed at least 2 cycles, and 100% if all 8 cycles were complete. Median PFS and OS were not reached. The regimen is well-tolerated as most AEs are G1 or G2. Compared to DA-R-EPOCH alone, the ORR is improved with fewer G3/G4 AEs. As the trial is ongoing, these results will be explored further within a larger cohort and with longer follow up time.