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. 2023 Jul 5;7(7):e917.
doi: 10.1097/HS9.0000000000000917. eCollection 2023 Jul.

Radiation and Dose-densification of R-CHOP in Primary Mediastinal B-cell Lymphoma: Subgroup Analysis of the UNFOLDER Trial

Gerhard Held  1 , Lorenz Thurner  2 , Viola Poeschel  2 , German Ott  3 , Christian Schmidt  4 , Konstantinos Christofyllakis  2 , Andreas Viardot  5 , Peter Borchmann  6 , Walburga Engel-Riedel  7 , Norbert Frickhofen  8 , Maike Nickelsen  9 , Ofer Shpilberg  10 , Mathias Witzens-Harig  11 , Frank Griesinger  12 , Beate Krammer-Steiner  13 , Andreas Neubauer  14 , Peter de Nully Brown  15 , Massimo Federico  16 , Bertram Glass  17 , Norbert Schmitz  18 , Gerald Wulf  19 , Lorenz Truemper  19 , Moritz Bewarder  2 , Niels Murawski  2 , Stephan Stilgenbauer  2 , Andreas Rosenwald  20 , Bettina Altmann  21 , Marianne Engelhard  22 , Heinz Schmidberger  23 , Jochen Fleckenstein  24 , Christian Berdel  24 , Markus Loeffler  21 , Marita Ziepert  21
Affiliations

Radiation and Dose-densification of R-CHOP in Primary Mediastinal B-cell Lymphoma: Subgroup Analysis of the UNFOLDER Trial

Gerhard Held et al. Hemasphere. .

Abstract

UNFOLDER (NCT00278408, EUDRACT 2005-005218-19) is a phase-3 trial in patients with aggressive B-cell lymphoma and intermediate prognosis, including primary mediastinal B-cell lymphoma (PMBCL). In a 2 × 2 factorial design, patients were randomized to 6× R-CHOP-14 or R-CHOP-21 (rituximab, cyclophosphamide, doxorubicin, vincristine, and prediso(lo)ne) and to consolidation radiotherapy to extralymphatic/bulky disease or observation. Response was assessed according to the standardized criteria from 1999, which did not include F-18 fluordesoxyglucose positron emission tomography/computed tomography (FDG-PET) scans. Primary end point was event-free survival (EFS). A subgroup of 131 patients with PMBCLs was included (median age, 34 y; 54% female, 79% elevated lactate dehydrogenase (LDH), 20% LDH >2× upper limit of normal [ULN], and 24% extralymphatic involvement). Eighty-two (R-CHOP-21: 43 and R-CHOP-14: 39) patients were assigned to radiotherapy and 49 (R-CHOP-21: 27, R-CHOP-14: 22) to observation. The 3-year EFS was superior in radiotherapy arm (94% [95% confidence interval (CI), 89-99] versus 78% [95% CI, 66-89]; P = 0.0069), due to a lower rate of partial responses (PRs) (2% versus 10%). PR triggered additional treatment, mostly radiotherapy (n = 5; PR: 4; complete response/unconfirmed complete response: 1). No significant differences were observed in progression-free survival (PFS) (95% [95% CI, 90-100] versus 90% [95% CI, 81-98]; P = 0.25) nor in overall survival (OS) (98% [95% CI, 94-100] versus 96% [95% CI, 90-100]; P = 0.64). Comparing R-CHOP-14 and R-CHOP-21, EFS, PFS, and OS were not different. A prognostic marker for adverse outcome was elevated LDH >2× ULN (EFS: P = 0.016; PFS: P = 0.0049; OS: P = 0.0014). With the limitation of a pre-PET-era trial, the results suggest a benefit of radiotherapy only for patients responding to R-CHOP with PR. PMBCL treated with R-CHOP have a favorable prognosis with a 3-year OS of 97%.

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Conflict of interest statement

GH has received grants from Roche and Bristol-Myers Squibb and personal fees from Bristol-Myers Squibb, Roche, Amgen, Spectrum and MSD. L Thurner has received travel grants from Abbvie, Janssen and EUSA-Pharm, and has indicated consultancy for Takeda, Astra-Zeneca, Merck, EUSA-pharm. VP has received grants from Deutsche Krebshilfe (German Cancer Aid), Chugai, Abbvie, Amgen, Roche, and Bristol-Myers Squibb. AV has received honoraria from Roche, Amgen, Kite, Gilead, Novartis, Bristol-Myers Squibb and has indicated a membership of the advisory board of Roche, Amgen, Kite, Gilead, Novartis, Bristol-Myers Squibb. MN has received travel grants from Roche, Celgene, and MSD and personal fees from Roche, Celgene, MSD, Janssen, Amgen, Incyte, and Abbvie. FG participates in advisory board of Roche, Boehringer Ingelheim, Abbvie, Merck, Takeda, MSD, Sanofi, Pfizer, Novartis, Amgen, and Janssen. PdNB has indicated consultancy for Roche, Incyte, and Novartis. SS has received grants from Abbvie, Astra-Zeneca, Celgene, Gilead, Roche, Janssen, Novartis, Morphosys and has indicated consultancy for for Abbvie, Astra-Zeneca, Celgene, Gilead, Roche, Janssen, Novartis, Morphosys; he has received drug/equipment supplied by entity from Abbvie, Astra-Zeneca, Celgene, Gilead, Roche, Janssen, Novartis, Morphosys. All the other authors have no conflicts of interest to disclose.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Event-free, progression-free, and overall survival. Graph shows EFS, PFS, and OS for all PMBCL patients (n = 131). EFS = event-free survival; OS = overall survival; PFS = progression-free survival; PMBCL = primary mediastinal B-cell lymphoma.
Figure 2.
Figure 2.
Event-free, progression-free, and overall survival according to the therapy arm. Graphs show event-free (A), progression-free (B), and overall survival (C) according to the radiotherapy arm or the observation arm (radiotherapy vs observation) and event-free (D), progression-free (E), and overall survival (F) according to the dose-densification (14 vs 21 d) for all PMBCL patients (n = 131). Hazard ratios for treatment effect adjusted for strata are presented for event-free and PFS. Due to the low number of events, adjusted hazard ratios for OS are not presented. OS = overall survival; PFS = progression-free survival; PMBCL = primary mediastinal B-cell lymphoma; R-CHOP = rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone; RTh = radiotherapy.
Figure 3.
Figure 3.
Event-free, progression-free, and overall survival according to the LDH groups. Graphs show event-free (A), progression-free (B), and overall survival (C) according to the LDH groups (above twice above the ULN yes/no) for all PMBCL patients with aaIPI = 1 (n = 109). Univariate hazard ratios are presented for event-free survival and PFS. Due to the low number of events, hazard ratio for OS is not presented. LDH = lactate dehydrogenase; OS = overall survival; PFS = progression-free survival; PMBCL = primary mediastinal B-cell lymphoma; ULN = upper limit of normal.
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