Persistence of minimal residual disease in bone marrow predicts outcome in follicular lymphomas treated with a rituximab-intensive program

Abstract

Key Points• PCR negativity is a strong outcome predictor after rituximab-intensive immunochemotherapy at multiple posttreatment times.• PCR is predictive even when maintenance is delivered, and accumulation of PCR-negative results further reduces the likelihood of relapse.We assessed the prognostic value of minimal residual disease (MRD) within the ML17638 phase 3 trial from the Fondazione Italiana Linfomi, investigating the role of rituximab maintenance in elderly follicular lymphoma (FL) patients after a brief first-line chemoimmunotherapy. MRD for the bcl-2/IgH translocation was determined on bone marrow cells in a centralized laboratory belonging to the Euro-MRD consortium, using qualitative and quantitative polymerase chain reactions (PCRs). Of 234 enrolled patients, 227 (97%) were screened at diagnosis. A molecular marker (MM) was found in 51%. Patients with an MM were monitored at 8 subsequent times. Of the 675 expected follow-up samples, 83% were analyzed. Conversion to PCR negativity predicted better progression-free survival (PFS) at all post-treatment times (eg, end of therapy: 3-year PFS, 72% vs 39%; P < .007). MRD was predictive in both maintenance (83% vs 60%; P < .007) and observation (71% vs 50%; P < .001) groups. PCR positivity at the end of induction was an independent adverse predictor (hazard ratio, 3.1; 95% confidence interval, 1.36-7.07). MRD is a powerful independent outcome predictor in FL patients who receive rituximab-intensive programs, suggesting a need to investigate its value for decision-making. This trial was registered at www.clinicaltrial.gov as #NCT01144364. (Blood. 2013;122(23):3759-3766) IntroductionTreatment of follicular lymphoma (FL) has advanced in recent years. Because of rituximab-supplemented chemotherapy, most patients currently achieve complete remission (CR), and overall survival (OS) rates have improved since the 1990s. However, most patients still relapse, and a proportion die of the disease. [1][2][3] The risk for recurrence is more pronounced among patients older than 60 years, as they often receive less-intense treatments. 4 Considerable evidence indicates that the persistence of polymerase chain reaction (PCR)-detectable residual tumor cells in the bone marrow (BM) and, to a lesser extent, peripheral blood is an independent predictor of relapse in FL 5-24 ; nevertheless, a few studies have failed to confirm this observation. [25][26][27][28] Concerns about the value of minimal residual disease (MRD) detection as an effective prognostic tool have been raised, particularly when applied to The results of this study were the subject of an oral presentation at the 2012 American Society of Hematology annual meeting.The online version of this article contains a data supplement.The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 USC section 1734. For personal use only. on May 10, 2018. by guest www.bloodjournal.org From r...

Minimal Residual Disease after Conventional Treatment Significantly Impacts on Progression-Free Survival of Patients with Follicular Lymphoma: The FIL FOLL05 Trial

“…However, a recent study from our group in old patients receiving R-FND followed by a brief consolidation with rituximab and a random between rituximab maintenance or observation showed power that MRD still retained an excellent prognostic discrimination among patients receiving rituximab maintenance (15). Moreover, our data suggest that a preemptive strategy similar to that used by the Nordic group in mantle cell lymphoma might appear of interest for future studies in follicular lymphoma, as also shown by the retrospective experience from our group (28).…”

“…Some authors reported that levels of BCL2/IGH <1 Â 10 À3 did not improve quality of response (14), whereas others showed that cases with low molecular tumor burden at diagnosis achieved CR more frequently than those with high molecular tumor burden (15). In our study, we demonstrated that cases displaying values <1 Â 10 À4 showed a clear advantage in terms of PFS (3-year PFS 80% vs. 59% for cases with higher molecular tumor burden; P ¼ 0.015) and ORR (76.6% vs. 38.9%; P ¼ 0.006).…”

“…Moreover, the percentage of cases with a molecular marker is superimposable to that previously reported by other authors (48%-54%; refs. (14,15,22).…”

“…In another study conducted by the Italian Lymphoma Group, MRD resulted as a powerful outcome predictor in patients receiving rituximab maintenance (15).…”

Autologous stem cell transplantation with in vivo purged progenitor cells shows long‐term efficacy in relapsed/refractory follicular lymphoma

“…To validate our molecular data, 54 samples of peripheral blood, bone marrow and apheresis were tested in the Laboratory of Molecular Biology in Turin belonging to the EURO-MRD consortium [9]. A qualitative PCR was conducted in blinded fashion for bcl-2 (MBR and mcr).…”