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• W2995780448 abstract "Historical outcomes remain poor for patients with relapsed/refractory diffuse large B-cell (DLBCL) and high-grade B-cell lymphoma (HGBCL) (Crump et al., 2017). Efforts to identify disease subsets at risk of poor outcomes have led to cell-of-origin classification, identification of high-risk molecular markers and, more recently, subtypes combining genetic, epigenetic and clinical features (Chapuy et al., 2018; Schmitz et al., 2018). Unfortunately, this has yet to translate into tailored therapy for poor-risk groups. The immunomodulatory drug lenalidomide has diverse mechanisms of action and efficacy across non-Hodgkin lymphoma (Gribben et al., 2015). Modest responses have been demonstrated in relapsed/refractory DLBCL, with an initial interest in disease of activated B-cell (ABC) origin (Witzig et al., 2011; Vose et al., 2013). Subsequent investigations have produced mixed results in this histology (Czuczman et al., 2017; Thieblemont et al., 2017). Data with lenalidomide are limited in other settings, including use in aggressive subtypes of DLBCL, such as transformed disease and disease with translocations of MYC, BCL2 and/or BCL6. To better understand the real-world efficacy of lenalidomide in relapsed/refractory DLBCL and to overcome limitations of eligibility within randomised trials, we conducted a retrospective analysis of all patients with DLBCL who were treated with lenalidomide at our institution. We included patients treated from 2011 to 2018, including those with transformed disease, patients with MYC, BCL2 and BCL6 translocations (including HGBCL), and patients treated with concurrent rituximab. Other combination therapies were excluded. Cell-of-origin was defined by the Hans algorithm (Hans et al., 2004). MYC, BCL2 and BCL6 translocations were identified by fluorescence in situ hybridisation (FISH). All pathology was reviewed internally by expert haematopathologists. Response was determined by Lugano criteria (Cheson et al., 2014). Progression-free survival (PFS) was defined as the time from lenalidomide initiation to disease progression. Overall survival (OS) was defined as the time from lenalidomide initiation to patient death. Kaplan-Meier estimates and the log-rank test were used to estimate and compare PFS and OS. The Cox proportional-hazards model was used to describe the potential effect of patient characteristics, treatment history and disease histology on response and survival. Sixty-two patients with DLBCL or HGBCL met the inclusion criteria, including 18 with histologically-confirmed transformed disease [16 from follicular lymphoma (FL) and two from marginal zone lymphoma]. Seven patients had a MYC translocation, with three classified as HGBCL. Using the Hans algorithm, 35 patients were classified as being germinal center B-cell (GCB) type, and 24 were non-GCB (three patients did not have sufficient IHC data to estimate cell-of-origin). The median age for initiation of lenalidomide was 73 years. Twenty-eight patients received concurrent rituximab. The majority of patients were initiated on a 25mg dose, although half of them required dose adjustments and 32% discontinued the drug due to toxicity (Table 1). Evaluating all patients, the objective response rate (ORR) was 43·5%. With a median follow-up of 10·5 months, the median PFS was 4·6 months with an OS of 14 months. There was no statistical difference in ORR, PFS or OS between patients with GCB and non-GCB de novo DLBCL (PFS 4 months vs. 5 months, P = 0·87, OS 7·8 months vs. 8·8 months, P = 0·99) (Fig 1). All patients n = 62 Non-GCB n = 23 De novo GCB n = 18 Transformed FL n = 16 For patients with transformed FL, ORR was 63%, PFS was 24 months and OS was 46·7 months. Compared to de novo DLBCL, OS was statistically prolonged (P = 0·02) (Fig 1). Though more patients with transformed FL were treated with concurrent rituximab compared to patients with de novo GCB disease, there was no difference in efficacy between patients treated with or without concurrent rituximab. Six out of seven patients with a MYC translocation achieved an objective response, including three with a complete response (CR). All three patients with HGBCL had an objective response, including two partial responses (PR) and one CR. This real-world analysis of lenalidomide did not reveal a difference in clinical activity based on cell-of-origin, as determined by the Hans algorithm. As suggested in previous studies, the Hans algorithm is not reliable in identifying responders to lenalidomide (Czuczman et al., 2017). However, gene expression may not be useful as a predictive marker either. Two randomised studies attempting to incorporate lenalidomide into first-line rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) for DLBCL were recently reported. In a cohort of ABC DLBCL cases, no difference in PFS was observed, either with or without lenalidomide (Vitolo et al., 2019). A PFS improvement was observed for R-CHOP combined with lenalidomide, over using R-CHOP alone in a smaller phase 2 study, enrolling all DLBCL cases, regardless of cellular origin. (Nowakowski et al., 2019). Together, these results suggest future studies incorporating lenalidomide should not focus solely on cell-of-origin. Durable clinical activity was observed in transformed FL, consistent with the known activity in low-grade FL (Leonard et al., 2019). In our study, patients with transformed FL had a median PFS of two years with an OS of nearly four years. Four patients remained in remission for a median of 21·1 months, despite having discontinued lenalidomide (range 13·6–33·1 months). Few studies have evaluated lenalidomide in transformed FL. A subset analysis of the NHL-003 study identified 23 patients with transformed FL and found an ORR of 57% with a PFS of 7·7 months (Czuczman et al., 2011). A second study revealed similar efficacy with lenalidomide given concurrently with rituximab (Wang et al., 2013). Our results suggest that lenalidomide should be considered in transformed FL patients who have not previously received lenalidomide. Six out of seven patients with a MYC translocation had an objective response, including the three patients with HGBCL. Such responses have not been well documented in the literature. One patient with ‘triple HIT’ disease had a complete response, which allowed the patient to receive chimeric antigen receptor T-cell therapy. While responses were of short duration for the heavily pre-treated DLBCL in this analysis, as described above, lenalidomide can serve as a bridge to consolidative cellular therapy in appropriate patients. A limitation of the study was that it was conducted in a single institution, though patients were treated by multiple physicians over a period of seven years. Patients were treated in a clinical setting with an active early phase clinical trial program. As such, patients had exhausted standard curative therapy and investigational options, limiting the selection bias. In conclusion, lenalidomide should be considered as a treatment option in relapsed/refractory high-risk DLBCL, regardless of cell-of-origin, transformed status, or the presence of a MYC translocation. Given responses in high-risk patients, additional combination studies with lenalidomide are warranted and should investigate predictors of response outside of the standard cell-of-origin paradigm." @default.
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• W2995780448 date "2019-12-17" @default.
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• W2995780448 title "Efficacy of lenalidomide in high‐risk diffuse large B‐cell lymphoma" @default.
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