Safety and Efficacy Of Bendamustine In Patients With Aggressive Non-Hodgkin Lymphomas (NHL)
Authors: Hammersen Jakob , Sommer Michael , Gössel Christin , Teichgräber Ulf , Hahnfeld Sabine , Scholl Sebastian , Fricke Hans-Jörg , Wedding Ulrich , Ekkehard Eigendorff , Iver Petersen , Merz Hartmut , Hochhaus Andreas , La Rosée Paul 
Published: October 2019

Abstract

Introduction
Frail patients with aggressive NHL frequently do not qualify for CHOP-based chemotherapy. Alternatives are required urgently. Bendamustine has been well established as a standard treatment of indolent lymphomas. Its use in high grade lymphoma has been suggested as a promising option. However, which patients benefit most effectively requires further clarification.

Methods
We retrospectively characterized 51 unselected consecutive patients (39,2% female, 60,8% male, median age 70 years, range 32 - 92 years) with aggressive NHL treated with bendamustine +/- rituximab. They were analyzed for baseline characteristics (histological type, IPI, ABC/GCB-subtypes, age, ECOG, comorbidity (CIRS-G), outcome (ORR, PFS, OS), and toxicity (CTCAE)).

Results
21 patients with aggressive NHL received Bendamustin as 1st-line therapy and 30 patients beyond 1st-line. Of the 1st line patients 14 suffered from diffuse large cell B cell lymphoma (DLCBL), 5 from mantle cell lymphoma (MCL), and 2 from other subtypes. In 1st line patients median age was 82 years, ECOG-status was ≥ 2 in 38%. Median international prognostic index (IPI) was 3 (range 1-4). Comorbidity assessment by CIRS-G revealed median 3 (range 1 to 5) severely or very severely affected organs. The overall response rate (ORR) in 1st line treatment was 91%, with a median progression free survival (PFS) of 6 months and a median overall survival (OS) of 15 month. In DLBCL 5 GCB- and 6 ABC-lymphomas were differentiated. GCB-patients showed an ORR of 80% (2 complete remission (CR), 2 partial remission PR)), a median PFS 8 month and OS of 15 months, respectively. ABC-patients had an ORR 67% (no CR, 4 PR, 2 SD), a median PFS of 6 month and OS of 8 months, respectively (n.s.). 7 patients achieved a long term-remission >5 years. Univariate analysis of prognostic variables showed significance for ECOG (p<0.0001) and CIRS-G (p=0.002) for OS, Cox-regression analysis showed significance for ECOG (p=0.016). No significance was shown for disease stage or LDH activities. The ORR in patients beyond 1st-line therapy (median age 64 years, ECOG-status ≥ 2 in 17%) was 66% with a median PFS of 8 month and OS of 24 month. Median cumulative dose was 540 mg/m2 in median 4 cycles.
Toxicity in the 1st-line cohort was moderate, mainly grade 1 & 2. Three patients showed grade 3 leukocytopenia. Other side effects primarily were: inappetence, weight-loss, fever.

Conclusion
Bendamustine shows high efficacy in aggressive NHL, even sustained remission was achieved by a subgroup, which requires further definition. Toxicity was well manageable. Defining prognostic parameters we showed GCB-subtype of DLBCL might predict a better outcome in bendamustine treated patients. Remarkably, performance and comorbidity assessment is of crucial prognostic value with a greater impact on outcome compared to classic parameters. Currently, the BRENDA trial (NCT01686321) prospectively investigates the role of bendamustine in aggressive NHL.

Disclosures:
Off Label Use: Use of Bendamustine in aggressive NHL. Wedding:Roche: Speakers Bureau; Amgen: Speakers Bureau; Chugai: Speakers Bureau; Janssen-Cilag: Speakers Bureau; Novartis: Speakers Bureau; Cephalon: Speakers Bureau; Prostarkan: Speakers Bureau; Pfizer: Speakers Bureau. La Rosée:Mundi Pharma: Honoraria.