Background: The AHL2011 study demonstrated that a PET-driven strategy allows to deescalate treatment to 4 x ABVD in PET negative patients after 2 cycles of escalated BEACOPP (BEACOPPesc) without loss of tumor control in patients with advanced Hodgkin lymphoma (HL) compared to a non PET-monitored treatment delivering 6 x BEACOPPesc (Casasnovas RO et al, Lancet Oncol 2019). The interim PET results after 2 (PET2) and 4 (PET4) cycles of chemotherapy were found to influence patients PFS and OS independently of IPS. To further refine the patients outcome prediction we evaluate the prognostic value of baseline Total Metabolic Tumor Volume (TMTV) and tumor dissemination (SDmax) in Ann Arbor stage III-IV patients included in the AHL2011 trial. Patients and methods: 634 patients enrolled in the AHL2011 trial with stage Ann Arbor III or IV were included in the study. According to the AHL2011 trial, patients were randomized in a standard arm (6 x BEACOPPesc) or a PET-driven arm (2 x BEACOPPesc and 4 x ABVD in negative PET2 patients or 4 x BEACOPPesc in positive PET2 patients). For each patient, a semi automatic tumor segmentation was retrospectively performed in baseline PET to calculate TMTV using the 41% of SUVmax threshold and compute the maximum distance between the delineated lesions normalized by body surface area (SDmax). Optimal thresholds for TMTV and SDmax were calculated using X-Tile and ROC curve approaches in a randomly assigned training (n=317) and validation sets (n=317). The per protocol PET2 and PET4 responses were analyzed using the modified Deauville criteria (positive if residual uptake >140% background liver). Multivariate analysis included treatment arm, TMTV, SDmax, international prognosis score (IPS), PET2, and PET4 as covariates. The median follow-up was 5.6y. Results : Median TMTV and SDmax were 215 ml and 0.221 m-1 in the whole population and similar in both randomized arms and in the training and validation sets. Optimal cutoffs were 220ml for TMTV (312 patients [49%] had High TMTV) and 0.330 m-1 for SDmax (149 patients [24%] had High SDmax) and similar in the training and validation sets. 5-year PFS for patients with TMTV>220ml was 84.1% vs 90.2% in low TMTV patients (p=0.02) in the whole population (in the training set: 83% vs 89%, p=0.088 ; in the validation set : 86% vs 92% p=0.11). 5-year PFS was significantly lower in patients with SDmax>0.333 m-1 (78.8% vs 89.7%; HR=2.15 [95%CI: 1.38-3.35], p=0.0005) in the whole population (in the training set: 77% vs 89%; p=0.0037); in the validation set: 81% vs 91; p=0.046). The combination of TMTV and SDmax allows to identify two subgroups of patients, those having both low TMTV and low SDmax (n= 281; 44%) and those having high TMTV and/or SDmax (5-year PFS: 92% vs 83.4%; HR=2.24 [95%CI: 1.39-3.62], p=0.0007) (figure 1). In multivariate analysis, high TMTV (p=0.034), high SDmax (p=0.0002), PET2 (p=0.02) and PET4 (p<0.001) positivity retained independent prognostic value for predicting PFS. Conclusion: Tumor burden (TMTV) and dissemination (SDmax) assessed on baseline 18FDG PET allow to predict, independently of early reponse to treatment, the outcome of patients with advanced HL. These two parameters overcome the prognosis value of IPS and could be included into new prognostic scores to tailor personalized therapy in advanced Hodgkin Lymphoma. Figure 1 : PFS according to TMTV and SDmax in stage III-IV HL patients enrolled in the AHL2011 study Figure 1 Figure 1. Disclosures Brice: Takeda: Consultancy, Honoraria, Research Funding; BMS: Honoraria; MSD: Honoraria. Ghesquieres: Janssen: Honoraria; Mundipharma: Consultancy, Honoraria; Roche: Consultancy; Celgene: Consultancy, Honoraria; Gilead Science: Consultancy, Honoraria. Stamatoullas-Bastard: Takeda: Consultancy. André: AbbVie: Other: Travel/accomodation/expenses; Roche: Other: Travel/accomodation/expenses, Research Funding; Johnson & Johnson: Research Funding; Incyte: Consultancy; Gilead: Consultancy, Other: Travel/Accommodations/Expenses; Karyopharm: Consultancy; Bristol-Myers-Squibb: Consultancy, Other: Travel/Accommodations/Expenses; Celgene: Other: Travel/accomodation/expenses; Takeda: Consultancy, Research Funding. Rossi: ROCHE: Honoraria, Research Funding; Takeda: Honoraria; JANSSEN: Honoraria; ABBVIE: Honoraria. Casasnovas: Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead Kite: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria.
Central nervous system (CNS) relapses are rare events in diffuse large B-cell lymphoma (DLBCL) that typically occur very early in the disease course, leading to poor survival rates. [1][2][3] Several identified risk factors include number and location of extranodal sites 2,4 ; factors identified by the 2016 CNS International Prognostic Index (CNS-IPI) 3 ; biologically, MYC gene rearrangements and double-/triple-hit lymphoma, [5][6][7] and more recently hypothesized specific genomic subtypes (eg, MYD88 L265P and CD79B mutations). 8 Prophylaxis for CNS relapses currently employs methotrexate (MTX), a blood-brain barrier-penetrating drug, 9 although the efficacy of intrathecal (IT) MTX is debated. 10,11 High-dose intravenous (HDIV) MTX seems more effective, especially in younger patients, but with significant toxicity/intolerability, notably in older patients with complex comorbidities and/or impaired renal function. 12-14 Identification of alternative agents that lower the incidence of CNS relapses is needed. 15
INTRODUCTION : Minimal residual disease (MRD) has emerged as an important predictor of clinical outcome in patients with mantle cell lymphoma (MCL). Its use in everyday clinical practice, however, remains uncertain since standardized MRD monitoring strategies and response criteria are not yet formally established. To address this question, we conducted the LyMa-MRD project as an ancillary biology study in a prospective phase III trial in MCL patients < 66 years of age (NCI NCT00921414; LyMa Trial; Le Gouill et al, NEJM 2017). Briefly, in this trial all patients were previously untreated and received 4 courses of R-DHAP followed by ASCT. After ASCT, patients were randomized between observation (obs) versus Rituximab maintenance (RM) which was associated to superior event free, progression free and overall survival, respectively. Herein, we present the final MRD analysis. METHODS : The final MRD analysis was performed in a total of 220 MRD evaluable patients [defined as patients with an available MRD assay and appropriate follow-up sample in peripheral blood (PB) and/or bone marrow, (BM), at the time point of interest for statistical analyses] and aimed to assess MRD response rates and prognostic impact [progression free and overall survival, (PFS, and OS, respectively)] at the pre-ASCT (after induction phase) (n=195 ; 86 RM and 84 obs) or (2 ; 90 RM and 92 obs). Sequential MRD monitoring was a predefined secondary objective. An additional aim was to assess the value of combining molecular MRD and PET (positron emission tomography) for outcome prediction pre- and post-ASCT. MRD was quantitatively assessed in PB and / or BM after induction or after ASCT by using gold standard EURO-MRD RQ-PCR assays targeted to clonal immunoglobulin gene rearrangements, in 3 French national reference laboratories. MRD data for survival analysis was generated from assays with a minimal sensitivity of at least 10-4. MRD status was assigned according to EURO-MRD interpretation guidelines. MRD negativity at a given time point was defined as absence of RQ-PCR amplification product in the follow-up sample (minimal assay sensitivity of 10-4). Non evaluable MRD was mostly due to no follow-up sample, no MRD target or MRD assay failure. RESULTS: In a total of 195 MRD evaluable patients who completed R-DHAP induction therapy, MRD was found negative in 77% (n=144) and 64% (n=115) of PB and BM samples, respectively. MRD status pre-ASCT was predictive of PFS and OS: p< 0.0001, respectively, for PB; p= 0.0295 and 0.0407, respectively, for BM). Post-ASCT, MRD in PB and BM was negative in 94% (n=181) and 81% (n=137) of patients, respectively, and was predictive of PFS (but not OS) (PB, p= 0.0452 ; BM, p=0.0261). In patients that were MRD negative either pre (PB, p= 0.0260; BM, p=0.0405) or post-ASCT (PB, p=0.001; BM, p=0.007), RM was associated to improved PFS and also OS, albeit to a lesser extent [pre-ASCT BM MRD and post-ASCT PB MRD neg groups only ; p= 0.0395 and p =0.02, respectively]. Finally, combining PET and MRD status offered improved prediction of PFS both pre- (p< 0.0001, PB; p=0.0028, BM MRD) and post-ASCT (p<0.0001, PB; p=0.0082, BM). Likewise, combining either pre- or post-ASCT PET/MRD also provided improved prediction of OS [PB, but not BM, plus PET pre-ASCT, p=0.0002 ; PB or BM MRD plus PET, p<0.0001 and p=0.0474, respectively, post-ASCT). CONCLUSION: Pre-ASCT MRD status in both BM and PB is an early predictor of PFS and OS in younger MCL patients receiving ASCT. RM provides longer PFS and OS regardless of MRD status pre- and post-ASCT. Early sequential MRD monitoring at the pre-ASCT treatment phase and directly post-ASCT thus offers strong potential for early clinical outcome prediction, as a surrogate clinical end point, and for MRD-guided, risk-adapted treatment in MCL. Disclosures Delfau-Larue: MUNDIPHARMA: Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); AMGEN: Honoraria; GILEAD: Honoraria; ROCHE: Honoraria. Thieblemont:Roche, Hospita: Research Funding; Roche, Amgen, Kyte Gilead, Celgene, Abbvie, Novartis, Cellectis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support; Cellectis: Speakers Bureau. Oberic:Roche, Janssen: Consultancy; Roche, Janssen: Other: Travel, Accommodations, Expenses; Roche: Honoraria. Bouabdallah:Gilead Sciences: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Roche: Consultancy, Honoraria. Casasnovas:MSD: Consultancy, Honoraria; AMGEN: Consultancy, Honoraria; BMS: Consultancy, Honoraria; abbvie: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding. Ribrag:BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses; argenX: Current equity holder in publicly-traded company, Research Funding; Infinity: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Honoraria; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; arGEN-X-BVBA: Research Funding; BAY1000394 studies on MCL: Patents & Royalties; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Eisai: Honoraria; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Immune Design: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy, Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AZD: Honoraria, Other; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Institut Gustave Roussy: Current Employment; Nanostring: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses; Pharmamar: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Hermine:Alexion: Research Funding; AB Science: Consultancy, Current equity holder in publicly-traded company, Honoraria, Patents & Royalties, Research Funding; Novartis: Research Funding; Roche: Consultancy; Celgene BMS: Consultancy, Research Funding. Le Gouill:Roche Genentech, Janssen-Cilag and Abbvie, Celgene, Jazz pharmaceutical, Gilead-kite, Loxo, Daiichi-Sankyo and Servier: Honoraria; Loxo Oncology at Lilly: Consultancy.
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