Safety and Early Efficacy of Obinutuzumab in Combination with Chemotherapy in Treatment Naive Patients with Follicular Lymphoma - Report of Polish Lymphoma Research Group (PLRG)
Authors: Paszkiewicz-Kozik Ewa , Hus Iwona , Palka Monika , Debowska Malgorzata , Konska Agnieszka , Kotarska Martyna , Tyczynska Agata , Joks Monika , Twardosz Maja , Giza Agnieszka , Wasik-Szczepanek Ewa , Kalicinska Elzbieta , Wisniewska Anna , Morawska Marta , Romejko-Jarosinska Joanna , Lewicka Barbara , Targonski Lukasz , Osowiecki Michal , Poplawska Lidia , Szymanski Marcin , Kruczkowska-Taranowicz Kamila , Drozd-Sokolowska Joanna , Swoboda Ryszard , Domanska-Czyz Katarzyna , Ostrowska Beata , Swierkowska Monika , Dabrowska-Iwanicka Anna Paulina , Druzd-Sitek Agnieszka , Konecki Robert , Borawska Anna , Dlugosz-Danecka Monika , Lech-Marańda Ewa , Walewski Jan 
Published: November 2021

Abstract
Introduction:
Obinutuzumab-based induction immunochemotherapy was demonstrated to improve the outcome of patients with follicular lymphoma (FL) comparing to the regimens with rituximab in GALLIUM study (NCT01332968). The infusion related reactions (IRRs) occur in more than half of FL patients during the first obinutuzumab administration. Therefore, during the whole treatment period infusions lasting more than 3-4 hours are so far recommended. Shorter infusions would be more convenient for both patients and medical staff and could also contribute to the shorter hospitalization that is desirable during COVID-19 pandemic. The aim of the study was to evaluate the tolerance and early efficacy of obinutuzumab-based regimens in FL patients in clinical practice.
Methods:
We evaluated tolerability of obinutuzumab infusions and response rates to different regimens of chemotherapy combined with obinutuzumab in consecutive FL patients treated in hemato-oncology centers in Poland from Jan 2020 to Jan 2021. Obinutuzumab was combined with CHOP, CVP or bendamustine according to the treating physician choice. Obinutuzumab maintenance was offered to the patients who achieved at least partial response (PR) after induction immunochemotherapy. Response was evaluated with computed tomography or positron emission tomography according to 2014 Lugano criteria. Adverse events were assessed according to Common Toxicity Criteria (version 5).
Results:
The study group included 129 treatment-naive FL patients. The median age (range) was 52 (29 - 90) years, 35.7% of patients were males. According to FLIPI 46.5 % of patients were classified as high risk, 33.3% as intermediate and 20.2% as low risk, whereas 33.7%, 30.4% and 35.9% of patients were in PRIMA PI high, intermediate and low risk groups, respectively, Table 1. Median number of GELF criteria was 2 (range 1-6). Induction chemotherapy included: CVP in 48.1% (n=62), CHOP in 29.5% (n=38) and Benda in 22.5% (n=29) of patients. Median number of cycles was 6 (range 1 - 8). Maintenance was started in 85 patients (76.6%). The first obinutuzumab dose was administered as a single infusion during the first day of the first cycle in 43.4% of patients (n=56), whereas 56.6 % (n=73) of patients had initial infusion divided into 2 days (100 mg and 900 mg). During the first cycle 93.8% (n=121) of patients received three doses of obinutuzumab. The doses were omitted in 8 patients: in 4 due to Covid-19, in 1 due to pneumonia and neutropenia and in 3 cases due to neutropenia. IRRs were reported during the first Obinutuzumab administration in 10.1% of patients (n=13, grade 1/2 in 11 and grade 3 in 2 patients): in 7 patients who received obinutuzumab initial dose in single infusion and in 6 patients who received first obinutuzumab dose divided in two days. Median time of the first infusions was 4 hours and 55 min (range 1:30 - 9:45). There were no IRRs reported during the subsequent obinutuzumab infusions. The most common adverse event was neutropenia with grade 3/4 events reported in 51.1% of patients (n=66). G-CSF support was given in 70.4% (n = 81/115), and as the primary prophylaxis in 42.6 % (n=49) of patients. The SARS-CoV-2 infection occurred in 19 patients regardless of initial chemotherapy regimen. After induction immunochemotherapy complete response (CR), partial response (PR), stable disease (SD) and progression disease (PD) rates were: 71.8%, 23.9%, 0.9% and 3.4%, respectively, Table 2.
With a median follow up of 8.7 months 5 patients (3.9%) relapsed, 4 died due to COVID infection. There were no deaths caused by FL.
Conclusions:
In our study obinutuzumab-based induction treatment was well tolerated. The low incidence and low grade of infusion related reactions in most of the patients, reported only during the first infusion, support the practice of administration of the first obinutuzumab dose in a single infusion. For convenience, the concept of short, 90 minutes infusion of Obinutuzumab starting from the second cycle could be considered (Canales MA, EHA 2021). During COVID-19 pandemic using obinutuzumab with chemotherapy is feasible and justified by the high response rate to this treatment.
Figure 1 Figure 1.

Disclosures
Paszkiewicz-Kozik: Roche: Honoraria, Other: congress fee; Servier: Other: congress fee; gillead: Other: travel grant; Takeda: Honoraria, Other: Travel Grants. Hus: Astra Zeneca: Honoraria, Research Funding; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees. Romejko-Jarosinska: roche: Other: congress fee; servier: Other: congress fee; gilead: Other: traver grant. Drozd-Sokolowska: AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees. Dlugosz-Danecka: Janssen: Consultancy, Research Funding; Roche: Consultancy, Research Funding, Speakers Bureau; Servier: Consultancy, Speakers Bureau; Acerta Pharma: Research Funding; AbbVie: Research Funding; Macrogenics: Research Funding; Beigene: Research Funding; MEI Pharma: Research Funding; Incyte Corp.: Research Funding; Takeda: Research Funding. Lech-Marańda: Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees. Walewski: Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Servier: Consultancy, Honoraria.