Search

Purpose: To evaluate the reliability of the Deauville score (DS) in therapy response assessment and to define the prognostic value of the metabolic response of end of induction (EOI) [ 18 F]FDG PET (PET) in follicular lymphoma patients., Methods: Adult patients with untreated grade 1-3a FL/ stage II-IV enrolled in the multicentre, prospective, phase III FOLL12 trial (NCT02063685) were randomized to receive standard immunochemotherapy followed by rituximab maintenance (standard arm) versus standard immunochemotherapy followed by response-adapted post-induction management (experimental arm). Baseline and EOI PET were mandatory for the study. All PET scans were centralized on the WIDEN® platform and classified according to DS in a blind independent central review. DS1-3 was considered negative (CMR), whereas DS4-5 was considered positive (not CMR). The primary endpoint was PFS. The main secondary endpoint was overall survival (OS)., Results: Overall, 807 follicular lymphoma patients-52% women, 89% stage III-IV disease, 40% with a high-risk FLIPI-2 score (3-5)-were enrolled in the study; 729 (90.4%) baseline and EOI PET were available for the analysis. EOI PET was positive (DS4-5) in 88/729 (12.1%) cases. Overall inter-reviewer agreement on PET pos/neg result was 0.92, while agreement on positive and negative cases was 0.77 and 0.94, respectively. The median follow-up was 69 months; 247 events were registered in the 5-yr follow-up, with a 5-yr PFS of 67% (95%CI: 63%-70%). The 5-yr PFS rate for PET neg (DS1-3) and PET pos (DS4-5) patients was 71% (95%CI: 67%-75%) and 36% (95%CI: 25%-46%), respectively, with HR 3.49 (95%CI: 2.57-4.72). Five-year PFS was worse as DS increased, with 74% (70%-78%), 58% (48%-67%; HR 1.71; p = 0.001)] and 36% (25%-46%; HR 3.88; p < 0.001) in DS1-2, DS3 and DS4-5, respectively. EOI PET maintained its prognostic value in both the standard and experimental arms. In the whole population, 5-yr OS was 94% (95%CI: 92%-96%), with 96% (95%CI: 94-97) and 82% (95%CI: 72%-89%) in EOI PET negative (DS1-3) and positive (DS4-5), respectively (HR 4.48; p < 0.001). When DS was associated with FLIPI-2, patients with DS3 or DS1-2 with high FLIPI-2 (3-5) experienced worse OS than patients with DS1-2 and low FLIPI-2 (1-2) (p = 0.003)., Conclusion: This study shows that DS is a reliable prognostic tool to evaluate EOI PET in follicular lymphoma patients, with prognostic value maintained both in the standard and experimental arms, making metabolic imaging a robust tool to assess response in FL. Moreover, although preliminary, this study provides further information on DS3 patients, who are considered as CMR but show a less favourable PFS than DS1-2 patients., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: The role of consolidation radiotherapy in patients with primary mediastinal B-cell lymphoma (PMBCL) is controversial., Methods: The IELSG37 trial, a randomized noninferiority study, aimed to assess whether irradiation can be omitted in patients with PMBCL with complete metabolic response (CMR) after induction immunochemotherapy. The primary end point was progression-free survival (PFS) at 30 months after random assignment. Patients with CMR were randomly assigned to observation or consolidation radiotherapy (30 Gy). With a noninferiority margin of 10% (assuming a 30-month PFS of 85% in both arms), a sample size of 540 patients was planned with 376 expected to be randomly assigned., Results: The observed events were considerably lower than expected; therefore, primary end point analysis was conducted when ≥95% of patients were followed for ≥30 months. Of the 545 patients enrolled, 268 were in CMR after induction and were randomly assigned to observation (n = 132) or radiotherapy (n = 136). The 30-month PFS was 96.2% in the observation arm and 98.5% in the radiotherapy arm, with a stratified hazard ratio of 1.47 (95% CI, 0.34 to 6.28) and absolute risk difference of 0.68% (95% CI, -0.97 to 7.46). The 5-year overall survival (OS) was 99% in both arms. Nonrandomized patients were managed according to local policies. Radiotherapy was the only treatment in 86% of those with Deauville score (DS) 4 and in 57% of those with DS 5. The 5-year PFS and OS of patients with DS 4 (95.8% and 97.5%, respectively) were not significantly different from those of randomly assigned patients. Patients with DS5 had significantly poorer 5-year PFS and OS (60.3% and 74.6%, respectively)., Conclusion: This study, the largest randomized trial of radiotherapy in PMBCL, demonstrated favorable outcomes in patients achieving CMR with no survival impairment for those omitting irradiation.

Background: A standard of care and optimal duration of therapy have not been established for patients with multiply relapsed or refractory follicular lymphoma. The aim of this study was to evaluate epcoritamab, a novel CD3 × CD20 bispecific antibody, in the third-line and later setting of follicular lymphoma., Methods: EPCORE NHL-1 is a multicohort, single-arm, phase 1-2 trial conducted at 88 sites across 15 countries. Here, we report the primary analysis of patients with relapsed or refractory follicular lymphoma in the phase 2 part of the trial, which included the pivotal (dose expansion) cohort and the cycle 1 optimisation cohort. Eligible patients were aged 18 years or older, had relapsed or refractory CD20 + follicular lymphoma (grade 1-3A), an Eastern Cooperative Oncology Group performance status of up to 2, and had received at least two previous lines of therapy (including an anti-CD20 monoclonal antibody and an alkylating agent or lenalidomide). Patients were treated with subcutaneous epcoritamab 48 mg in 28-day cycles: weekly in cycles 1-3, biweekly in cycles 4-9, and every 4 weeks until disease progression or unacceptable toxicity. To mitigate the risk and severity of cytokine release syndrome, in the pivotal cohort, cycle 1 consisted of a step-up dosing regimen of a 0·16-mg priming dose on day 1 and a 0·80-mg intermediate dose on day 8, followed by subsequent 48-mg full doses and prophylactic prednisolone 100 mg; in the cycle 1 optimisation cohort, a second intermediate dose of 3 mg on day 15, adequate hydration, and prophylactic dexamethasone 15 mg were evaluated during cycle 1 to further reduce risk and severity of cytokine release syndrome. Primary endpoints were independently reviewed overall response rate for the pivotal cohort and the proportion of patients with grade 2 or worse and any-grade cytokine release syndrome for the cycle 1 optimisation cohort. Analyses were done in all enrolled patients who had received at least one dose of epcoritamab. This study is registered with ClinicalTrials.gov, NCT03625037, and is ongoing., Findings: Between June 19, 2020, and April 21, 2023, 128 patients (median age 65 years [IQR 55-72]; 49 [38%] female and 79 [62%] male) were enrolled and treated in the pivotal cohort (median follow-up 17·4 months [IQR 9·1-20·9]). The overall response rate was 82·0% (105 of 128 patients; 95% CI 74·3-88·3), with a complete response rate of 62·5% (80 of 128; 95% CI 53·5-70·9). The most common grade 3-4 treatment-emergent adverse event was neutropenia in 32 (25%) of 128 patients. Grade 1-2 cytokine release syndrome was reported in 83 (65%) of 128 patients; grade 3 cytokine release syndrome was reported in two (2%). Immune effector cell-associated neurotoxicity syndrome was reported in eight (6%) of 128 patients (five [4%] grade 1; three [2%] grade 2). Between Oct 25, 2022, and Jan 8, 2024, 86 patients (median age 64 years [55-71]; 37 [43%] female and 49 [57%] male) were enrolled and treated in the cycle 1 optimisation cohort. The incidence of cytokine release syndrome was 49% (42 of 86 patients; eight [9%] grade 2; none of grade 3 or worse), with no reported immune effector cell-associated neurotoxicity syndrome., Interpretation: Epcoritamab monotherapy showed clinically meaningful activity in patients with multiply relapsed or refractory follicular lymphoma, and had a manageable safety profile., Funding: Genmab and AbbVie., Competing Interests: Declaration of interests KML declares being a member of the Epcoritamab Global Council on behalf of Genmab; a consulting or advisory role for AbbVie, BeiGene, BMS, Genmab, Kite/Gilead, and Roche; participation in speakers bureaus from AbbVie and BMS; research funding (paid to institution) from AbbVie, ADC Therapeutics, AstraZeneca, BeiGene, BMS, CellCentric, Genmab, Janssen, Kite/Gilead, MorphoSys, MSD, Nurix, Regeneron, Roche, Step Pharma, and Viracta; and travel expenses from BMS. UV declares participation on an advisory board for AbbVie, Bayer, Genmab, Gilead, and Novartis; and lecture fees from AbbVie, Incyte, Janssen, Regeneron, Roche, and Servier. WJ declares research funding and consultancy fees from AbbVie and Roche. PJL declares research grants from Takeda and Servier; advisory honoraria from BMS, Roche, Takeda, Genmab, AbbVie, Incyte, Regeneron, and Sandoz; and consultancy honoraria from Y-mAbs Therapeutics. EG declares congress or travel fees or hospitality from AbbVie, Amgen, Gilead, Roche, and Sanofi; research funding from MSD, Novartis, Sandoz, and Sanofi; is a coordinating investigator for industry-sponsored studies for Astellas, Pharmacyclics, and Roche; and has received honoraria from Alexion, BMS, EUSA Pharma, Gilead, Jazz Pharma, Novartis, Pfizer, Roche, Sandoz, and Sanofi. AS declares consultancy for Takeda, BMS, Novartis, Janssen, MSD, Amgen, GSK, Sanofi, Kite, and Mundipharma; honoraria from Takeda, BMS, Novartis, Janssen, MSD, Amgen, GSK, Sanofi, and Kite; membership on board of directors or advisory committee for Takeda, BMS, Novartis, Janssen, Amgen, Bluebird, Sanofi, and Kite; travel expenses from Takeda, BMS, and Roche; research funding from Takeda; and participation in speakers bureaus for Takeda, BMS, Novartis, Janssen, MSD, Amgen, GSK, Sanofi, and Kite. BH declares membership on board of directors or advisory committee for ADC Therapeutics and BMS. HT declares membership on board of directors or advisory committee for ADC Therapeutics, BMS, and Roche; honoraria from Roche; and research funding from Roche. RC declares consultancy for AbbVie, Janssen, AstraZeneca, Kite, BMS, Genmab, Roche, Takeda, Kyowa Kirin, BeiGene, and Lilly; participation in speakers bureaus for AbbVie, Janssen, AstraZeneca, Kite, BMS, Roche, and Takeda; and research funding from Pfizer. DJL declares participation on advisory boards and consultancy for Janssen, Lilly, Roche, BeiGene, and Kite. MH declares participation on scientific advisory boards for AbbVie, BMS, Genmab, Janssen, Roche, and Takeda; and research support (paid to institution) from BMS, Genentech, Genmab, Incyte, Janssen, Novartis, Roche, and Takeda. MRC declares consultancy for AbbVie, Janssen, Gilead, AstraZeneca, Genmab, and Incyte; participation on advisory boards for AbbVie, Janssen, Gilead, and Genmab; and travel expenses from AbbVie, Janssen, AstraZeneca, Genmab, Roche, and Pfizer. J-MS declares consultancy or an advisory role for AbbVie, BeiGene, BMS, Gilead/Kite, Incyte, Janssen, Lilly, Miltenyi Biomedicine, Novartis, and Roche; and speaker honoraria from AbbVie, BeiGene, BMS, Gilead/Kite, Incyte, Janssen, Lilly, Novartis, and Roche. TC declares research funding from BeiGene; and participation in a speakers bureau for Janssen-Cilag. SL declares membership on board of directors or advisory committee for BeiGene, Genmab, Gilead, Incyte, Novartis, Orion, and Roche; research funding (paid to institution) from Bayer, BMS, Genmab, Hutchmed, Novartis, Nordic Nanovector, and Roche; and honoraria from Gilead, Incyte, and Novartis. MEDC declares consultancy for AbbVie, Novartis, and Sanofi; and research funding from BMS, Gilead, and Genmab. DG, YL, DH, and EF are current employees of Genmab. IA and TA are current employees of Genmab and hold stock or options in Genmab. MHD is a current employee of AbbVie. BE is a current employee of Genmab and holds patents and royalties (P158-US-PSP3). CT declares research funding from BMS, Hospira, and Roche; consultancy for AbbVie, Amgen, BMS, Cellectis, Gilead, Kite, Novartis, and Roche; honoraria from AbbVie, Amgen, Bayer, Cellectis, Gilead, Incyte, Janssen, Kite, Novartis, and Takeda; membership on board of directors or advisory committee for AbbVie, Amgen, BMS, Cellectis, Gilead, Incyte, Janssen, Kite, Novartis, Roche, and Takeda; and travel expenses from AbbVie, Amgen, BMS, Cellectis, Gilead, Kite, Novartis, and Roche. JMV declares research funding from Epizyme, Genmab, and Loxo; and consultancy for Adaptive, Genmab, and Ono. All other authors declare no competing interests., (2024 Elsevier Ltd. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Abstract: Primary testicular diffuse large B-cell lymphoma (PTL) is characterized by high risk of contralateral testis and central nervous system (CNS) relapse. Chemoimmunotherapy with intrathecal (IT) CNS prophylaxis and contralateral testis irradiation eliminates contralateral recurrences and reduces CNS relapses. The IELSG30 phase 2 study investigated feasibility and activity of an intensified IT and IV CNS prophylaxis. Patients with stage I/II PTL who had not received treatment received 2 cycles of IV high-dose methotrexate (MTX) (1.5 g/m2) after 6 cycles of the R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, every 21 days). IT liposomal cytarabine was administered on day 0 of cycles 2 to 5 of 21-day R-CHOP regimen. Contralateral testis radiotherapy (25-30 Gy) was recommended. Fifty-four patients (median age: 66 years) with stage I (n = 32) or II (n = 22) disease were treated with R-CHOP, 53 received at least 3 doses of IT cytarabine, 48 received at least 1 dose of IV MTX, and 50 received prophylactic radiotherapy. No unexpected toxicity occurred. At a median follow-up of 6 years, there was no CNS relapse; 7 patients progressed, and 8 died, with 5-year progression-free and overall survival rates of 91% (95% confidence interval [CI], 79-96) and 92% (95% CI, 81-97), respectively. Extranodal recurrence was documented in 6 patients (in 2 without nodal involvement). In 4 cases, the relapse occurred >6 years after treatment. Causes of death were lymphoma (n = 4), second primary malignancy (n = 1), cerebral vasculopathy (n = 1), unknown (n = 2). Intensive prophylaxis was feasible and effective in preventing CNS relapses. Late relapses, mainly at extranodal sites, represented the most relevant pattern of failure. This trial was registered at www.clinicaltrials.gov as #NCT00945724., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: Optimal consolidation for young patilents with relapsed/refractory (R/R) follicular lymphoma (FL) remains uncertain in the rituximab era, with an unclear benefit of autologous stem cell transplantation (ASCT). The multicenter, randomized, phase III FLAZ12 (NCT01827605) trial compared anti-CD20 radioimmunotherapy (RIT) with ASCT as consolidation after chemoimmunotherapy, both followed by rituximab maintenance., Patients and Methods: Patients (age 18-65 years) with R/R FL and without significant comorbidities were enrolled and treated with three courses of conventional, investigator-chosen chemoimmunotherapies. Those experiencing at least a partial response were randomized 1 : 1 to ASCT or RIT before CD34+ collection, and all received postconsolidation rituximab maintenance. Progression-free survival (PFS) was the primary endpoint. The target sample size was 210 (105/group)., Results: Between August 2012 and September 2019, of 164 screened patients, 159 were enrolled [median age 57 (interquartile range 49-62) years, 55% male, 57% stage IV, 20% bulky disease]. The study was closed prematurely because of low accrual. Data were analyzed on 8 June 2023, on an intention-to-treat basis, with a 77-month median follow-up from enrollment. Of the 141 patients (89%), 70 were randomized to ASCT and 71 to RIT. The estimated 3-year PFS in both groups was 62% (hazard ratio 1.11, 95% confidence interval 0.69-1.80, P = 0.6662). The 3-year overall survival also was similar between the two groups. Rates of grade ≥3 hematological toxicity were 94% with ASCT versus 46% with RIT (P < 0.001), and grade ≥3 neutropenia occurred in 94% versus 41%, respectively (P < 0.001). Second cancers occurred in nine patients after ASCT and three after radioimmunotherapy (P = 0.189)., Conclusions: Even if prematurely discontinued, our study did not demonstrate the superiority of ASCT versus RIT. ASCT was more toxic and demanding for patients and health services. Both strategies yielded similar, favorable long-term outcomes, suggesting that consolidation programs milder than ASCT require further investigation in R/R FL., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)