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

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.

Multicenter, Open-Label, Phase II Study of Bendamustine and Rituximab Followed by 90-Yttrium (Y) Ibritumomab Tiuxetan for Untreated Follicular Lymphoma (Fol-BRITe)

“…All 39 patients were tested at baseline, but only 12 (31%) were positive for BCL2 gene rearrangement. This is a much lower rate of BCL2 positivity than the 62% to 68% reported in the literature (21)(22)(23). Although 100% of patients who had detectable BCL2 by PCR at baseline became undetectable for BCL2-IGH translocation after 4 cycles of BR, and remained undetectable after RIT, the sensitivity of our assay may not be able to detect a true MRD state.…”

The Minimal Residual Disease in Non-Hodgkin's Lymphomas: From the Laboratory to the Clinical Practice

“…To the same conclusion went also another small and retrospective study assessing MRD in a series of 48 FL patients receiving R-Bendamustine as first-line therapy: 93% of patients became MRD-negative after treatment, and the MRD-negativity at 6 months played a favorable prognostic impact on the 30 months PFS (80% for MRD-negative cases vs. 46% for MRD-positive ones). The median clearance of molecular disease was 3 logs, a value higher than that observed in the Foll05 or Zeus trials (37).…”

Follicular lymphoma: results of multicenter study of first-line therapy with bendamustine and rituximab, risk factors for adverse events (fl-rus-2013 protocol)

“…Основной конечной точкойисследованиявыбранаБПВ. 6,0 (1,9-12,0) схемынеопределены.Анализмеждународныхисследований показывает [17,18,32], что режим R-B в сравнении с курсом R-CHOP позволяет достичь высокогопроцентаполныхремиссийФЛприсравнительноменьшейтоксичности. Результатыпроводимогомногоцентровогоиссле-дованияприменениякомбинированнойтерапии1-й линиибендамустиномиритуксимабомспоследующей поддерживающейтерапиейритуксимабомубольных ФЛдемонстрируют,чтоданнаясхематерапиипозволяет в 61 % случаев достичь полной ремиссии ив20%-частичнойремиссиизаболеванияупациентовсреднегоипожилоговозраста(медианавозраста-59лет(30-78лет);48%больных,включенных висследование,старше60лет).Процентполныхре-миссийвисследованиинафонетерапииR-Bсовпадаетсрезультатамимеждународныхисследований:61 и63% [18].ПритерапииR-CHOPпроцентполных ремиссийсоставляет66% [18] работе встречались в 16% случаев, в исследовании P. Mondello -в 3% при терапии R-B против 57 % притерапииR-CHOP.Такимобразом,минимальные осложнения курса R-B терапии, а также отсутствие осложненийсосторонысердечно-сосудистойиэндокриннойсистемдаютправосмелорекомендоватькурс R-Bкаккурсвыборавтерапиипожилыхпациентов, имеющихсопутствующуюпатологию.…”