The Combination of Rituximab and Bendamustine as First-Line Treatment Is Highly Effective in the Eradicating Minimal Residual Disease in Follicular Lymphoma: An Italian Retrospective Study

Sara Galimberti; Elena Ciabatti; Giacomo Ercolano; Susanna Grassi; Francesca Guerrini; Nadia Cecconi; Martina Rousseau; Giulia Cervetti; Francesco Mazziotta; Lorenzo Iovino; Franca Falzetti; Flavio Falcinelli; Alberto Bosi; Luigi Rigacci; Sofia Kovalchuk; Daniele Vallisa; Lucia Macchia; Eugenio Ciancia; Mario Petrini

doi:10.3389/fphar.2017.00413

The Combination of Rituximab and Bendamustine as First-Line Treatment Is Highly Effective in the Eradicating Minimal Residual Disease in Follicular Lymphoma: An Italian Retrospective Study

Front Pharmacol. 2017 Jun 29:8:413. doi: 10.3389/fphar.2017.00413. eCollection 2017.

Authors

Sara Galimberti¹, Elena Ciabatti¹, Giacomo Ercolano¹, Susanna Grassi^{1

2}, Francesca Guerrini¹, Nadia Cecconi¹, Martina Rousseau¹, Giulia Cervetti¹, Francesco Mazziotta¹, Lorenzo Iovino¹, Franca Falzetti³, Flavio Falcinelli³, Alberto Bosi⁴, Luigi Rigacci⁴, Sofia Kovalchuk⁴, Daniele Vallisa⁵, Lucia Macchia¹, Eugenio Ciancia⁶, Mario Petrini¹

Affiliations

¹ Section of Hematology, Department of Clinical and Experimental Medicine, University of PisaPisa, Italy.
² Doctoral School of Genetics, Oncology and Clinical Medicine (GeNOMEC), University of SienaSiena, Italy.
³ Department of Hematology, University of PerugiaPerugia, Italy.
⁴ Department of Hematology, University of FirenzeFirenze, Italy.
⁵ Department of Hematology and Oncology, Azienda Unità Sanitaria Locale di PiacenzaPiacenza, Italy.
⁶ Pathology, Azienda Ospedaliero Universitaria PisanaPisa, Italy.

Abstract

R-Bendamustine is an effective treatment for follicular lymphoma (FL). Previous large trials demonstrated the prognostic role of the molecular minimal residual disease (MRD) during the most frequently adopted chemotherapeutic regimens, but there are not yet conclusive data about the effect of combination of rituximab (R) and bendamustine in terms of MRD clearance. Thus, the aim of this retrospective study was to assess if and in what extent the combination of rituximab and bendamustine would exert a significant reduction of the molecular disease in 48 previously untreated FL patients. The molecular marker at baseline was found in the 62.5% of cases; no significant differences were observed between patients with or without the molecular marker in respect of the main clinical features. Moreover, the quantization of the baseline molecular tumor burden showed a great variability: the median value was 1.4 × 10^-2 copies, ranging from 3 × 10^-5 to 4 × 10⁴. The initial molecular tumor burden did not correlate with clinical features and did not impact on the subsequent quality of response. After treatment, 93% of cases became MRD-negative; the median reduction of the BCL2/JH load was 4 logs. The 2-years PFS was 85%; it was significantly longer for patients in complete than for those in partial response (91 vs. 57%; p = 0.002), and for cases with lower FLIPI-2 score (88 vs. 60%; p = 0.004). On the contrary, PFS did not differ between patients with or without the molecular marker at baseline; a molecular tumor burden 15 times higher was observed in the relapsed subgroup in comparison to the relapse-free one, but this difference did not change the PFS length. The 2-years OS was 93.6%; the only variable that significantly impacted on it was the FLIPI-2 score; the presence of the molecular marker at baseline or its behavior after treatment did not impact on survival. This study, even if retrospective and conducted on a small series of patients, would represent a proof of concept that R-bendamustine is able to so efficaciously eradicate MRD that it could be able to by-pass the prognostic significance of MRD already demonstrated for other chemotherapeutic regimens in FL.

Keywords: BCL2/IGH; MRD; PCR; bendamustine; follicular lymphoma; rituximab.