Consolidation Anti-CD22 Fractionated Radioimmunotherapy with 90y-Epratuzumab Tetraxetan Following R-CHOP in Elderly DLBCL Patients: A Lysa Phase II Prospective Trial
Authors: Kraeber-Bodere Françoise , Pallardy Amandine , Le Gouill Steven , Maisonneuve Hervé , Lamy Thierry , Bouabdallah Krimo , Milpied Noel , Jardel Henry , Deconinck Eric , Morineau Nadine , Foussard Charles , Brion Annie , Gressin Remy , Tournilhac Olivier , Gyan Emmanuel , Moreau Anne , Berthou Christian , Dreyfus Francois , Bodet-Milin Caroline , Cazeau Anne-Laure , Garin Etienne , Vuillez Jean-Philippe , Campion Loic , Moreau Philippe , Wegener William A , Goldenberg David M , Soubeyran Pierre 
Published: October 2019

Abstract
Abstract 906

Background:
Consolidation using radioimmunotherapy (RIT) is a promising approach for elderly patients with diffuse large B-cell lymphoma (DLBCL) who are ineligible for autologous stem-cell transplantation. RIT using fractionated injections of 90Y-epratuzumab tetraxetan (Immunomedics, Inc.), a radiolabeled humanized anti-CD22 antibody, has been evaluated in relapsed patients with indolent or aggressive non-Hodgkin lymphoma (NHL), providing long-term disease control with manageable hematologic toxicities (Morschhauser et al., J Clin Oncol. 2010;28(23);3709-16). A French phase II trial sponsored by the LYSA group now assessed front-line treatment using fractionated RIT with 90Y-epratuzumab tetraxetan as consolidation therapy after R-CHOP in previously untreated elderly (age >60 years) patients presenting with stage I/II bulky or stage III/IV DLBCL.

Methods:
The trial included 6 courses of R-CHOP delivered q2wks followed by 2 infusions of 90Y-epratuzumab tetraxetan (2 × 15 mCi/m2 [555 MBq/m2], 7 days apart), 8 wks later. Patients were enrolled at time of diagnosis.

Results:
From October 2008 to December 2010, 75 patients (41 males, 34 females) have been accrued prospectively at 19 French institutions. The median age was 69 (range, 60–79 years); 57 patients (76.0%) were Ann Arbor stage III/IV. Seventy-one of the 75 completed 6 courses of R-CHOP-14 and 61/75 (81.2%) were eligible for RIT. Thus, 14 patients were considered ineligible for RIT because of R-CHOP toxicity (N= 5), progressive disease (PD, N=3), patient refusal (N=3), or concomitant illness (N=3). RIT toxicity consisted of grade 3–4 hematologic toxicity in 51/61 patients (83.6%): grade 3–4 neutropenia in 46 (75.4%), grade 3–4 anemia in 15 (24.6%), and grade 3–4 thrombocytopenia in 47 (77.0%), with a nadir at 42, 48, and 43 days after RIT and a median duration of 18, 5, and 17 days, respectively. Following RIT, RBC and/or platelet transfusions were given to 31 patients (50.8 %). Serious febrile neutropenia was observed in 13 cases (17.3 %) after R-CHOP and in 3 patients (4.9%) following RIT. RIT's severe non-hematologic toxicity consisted of grade 4 gastrointestinal in 1 patient (1.6 %) and grade 4 infection in 3 (4.9%). No patient had mucositis after RIT. In the follow-up, 2 patients (2.6%) developed myelodysplastic syndrome 5 and 20 months after RIT.
Using the 1999 International Workshop for Response Criteria for NHL (Cheson 1999), the overall response rate (ORR) after 6 × R-CHOP14 was 94.6% (71/75); 52 patients (69.3%) achieved CR/CRu and 19 (25.3%) had a partial response (PR). Among the 4 remaining patients, one had stable disease and 2 had PD; no assessment was obtained in the other. In an intention-to-treat analysis, CR/CRu rate after 6 × R-CHOP14 followed by RIT was 72.0% (N=54). Seven patients (9.3%) remained in PR and 8 (10.7%) progressed (2 patients previously in PR with PET-positive findings, 3 previously in CRu, including 1 PET-positive, and 3 in PD before RIT and then ineligible for RIT). No response assessment was obtained in the 6 others ineligible for RIT. At a median follow-up of 24 months (range, 1–46), 18 patients experienced lymphoma progression and/or a related death, yielding an estimated 2-year event-free-survival (EFS) of 73.3% (60.7-82.5%) and an estimated 2-year overall survival (OS) of 83.2% (71.4-90.4%). For the 61 patients who received 6 courses of R-CHOP followed by RIT consolidation, ORR was 91.8% (56/61); 50 patients (81.9%) achieved CR/CRu. Eight of 16 patients (50.0%) who had less than a CR/CRu with R-CHOP converted to CR/CRu after RIT. According to a PET analysis (Cheson 2007; N=55), 12 of the 24 patients (50.0%) who were not PET-negative after R-CHOP improved their metabolic response after RIT, resulting in a CR rate of 72.7%. Among these 61 patients, 12 experienced progression and/or a related death, yielding an estimated 2-year EFS of 78.7% (65.1–87.4%) and an estimated 2–year OS of 90.1% (77.7–95.8%).

Conclusions:
This phase II study clearly shows that fractionated RIT with 90Y-epratuzumab as a consolidation therapy after 6 × R-CHOP-14 is feasible and tolerable in elderly untreated DLBCL patients with advanced disease. RIT markedly improved response status observed after 6 × R-CHOP14. EFS data achieved with R-CHOP plus RIT compare favourably with those achieved with R-CHOP alone in the same patient population.

Disclosures:
Wegener: Immunomedics: Employment. Goldenberg:Immunomedics: Employment, Equity Ownership.