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. 2023 Jul 5;7(7):e904.
doi: 10.1097/HS9.0000000000000904. eCollection 2023 Jul.

Radiation and Dose-densification of R-CHOP in Aggressive B-cell Lymphoma With Intermediate Prognosis: The UNFOLDER Study

Lorenz Thurner  1 , Marita Ziepert  2 , Christian Berdel  3 , Christian Schmidt  4 , Peter Borchmann  5 , Dominic Kaddu-Mulindwa  1 , Andreas Viardot  6 , Mathias Witzens-Harig  7 , Judith Dierlamm  8 , Mathias Haenel  9 , Bernd Metzner  10 , Gerald Wulf  11 , Eva Lengfelder  12 , Ulrich B Keller  13 , Norbert Frickhofen  14 , Maike Nickelsen  15 , Tobias Gaska  16 , Frank Griesinger  17 , Rolf Mahlberg  18 , Reinhard Marks  19 , Ofer Shpilberg  20 , Hans-Walter Lindemann  21 , Martin Soekler  22 , Ludwig Fischer von Weikersthal  23 , Michael Kiehl  24 , Eva Roemer  25 , Martin Bentz  26 , Beate Krammer-Steiner  27 , Ralf Trappe  28 , Peter de Nully Brown  29 , Massimo Federico  30 , Francesco Merli  31 , Marianne Engelhard  32 , Bertram Glass  33 , Norbert Schmitz  34 , Lorenz Truemper  11 , Moritz Bewarder  1 , Frank Hartmann  1 , Niels Murawski  1 , Stephan Stilgenbauer  1 , Andreas Rosenwald  35 , Bettina Altmann  2 , Heinz Schmidberger  36 , Jochen Fleckenstein  3 , Markus Loeffler  2 , Viola Poeschel  1 , Gerhard Held  37
Affiliations

Radiation and Dose-densification of R-CHOP in Aggressive B-cell Lymphoma With Intermediate Prognosis: The UNFOLDER Study

Lorenz Thurner et al. Hemasphere. .

Abstract

UNFOLDER (Unfavorable Young Low-Risk Densification of R-Chemo Regimens) is an international phase-3 trial in patients 18-60 years with aggressive B-cell lymphoma and intermediate prognosis defined by age-adjusted International Prognostic Index (aaIPI) of 0 and bulky disease (≥7.5 cm) or aaIPI of 1. In a 2 × 2 factorial design patients were randomized to 6× R-CHOP-14 or 6× R-CHOP-21 (rituximab, cyclophosphamide, doxorubicin, vincristine, and prediso[lo]ne) and to consolidation radiotherapy to extralymphatic and bulky disease or observation. Response was assessed according to the standardized response criteria published in 1999, not including F-18 fluordesoxyglucose positron emission tomography/computed tomography (FDG-PET). Primary endpoint was event-free survival (EFS). A total of 695 of 700 patients were eligible for the intention-to-treat analysis. Totally 467 patients qualified for radiotherapy of whom 305 patients were randomized to receive radiotherapy (R-CHOP-21: 155; R-CHOP-14: 150) and 162 to observation (R-CHOP-21: 81, R-CHOP-14: 81). Two hundred twenty-eight patients not qualifying for radiotherapy were randomized for R-CHOP-14 versus R-CHOP-21. After a median observation of 66 months 3-year EFS was superior in the radiotherapy-arm versus observation-arm (84% versus 68%; P = 0.0012), due to a lower rate of partial responses (PR) (2% versus 11%). PR often triggered additional treatment, mostly radiotherapy. No significant difference was observed in progression-free survival (PFS) (89% versus 81%; P = 0.22) and overall survival (OS) (93% versus 93%; P = 0.51). Comparing R-CHOP-14 and R-CHOP-21 EFS, PFS and OS were not different. Patients randomized to radiotherapy had a superior EFS, largely due to a lower PR rate requiring less additional treatment (NCT00278408, EUDRACT 2005-005218-19).

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Conflict of interest statement

L. Thurner has received travel grants from Abbvie, Janssen and EUSA-Pharm, and has indicated consultancy for Takeda, Astra-Zeneca, Merck, EUSA-pharm. DK-M has received personal fees from Novartis, Astra-Zeneca, Gilead Sciences, GlaxoSmithKline, Janssen-Cilag, and nonfinancial support from Gilead Sciences, Janssen-Cilag, Takeda, Novartis. 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. UBK has received honoraria and advisory fees from Roche, Janssen-Cilag, Takeda, Bristol-Myers Squibb, Gilead, Hexal, Pfizer, Astra- Zeneca, Pentixapharm, Amgen, Novartis, MSD and has received clinical study support for Celgene, Takeda, BMS, Roche, Astra-Zeneca, Novartis, MSD, Janssen-Cilag, Pfizer. 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. RT has received grants from Atara and Roche and travel support from Roche, Atara, Celgene, Janssen and Abbvie; he has indicated a membership of the advisory board of Atara and Abbvie and has indicated consultancy for s Atara. PdNB has indicated consultancy for Roche, Incyte and Novartis. FM has received travel grants from Roche, Takeda, Janssen and Gilead and has indicated consultancy and advisory role for Roche, Gilead, Janssen, MSD, Takeda 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. VP has received grants from Deutsche Krebshilfe (German Cancer Aid), Chugai, Abbvie, Amgen, Roche and Bristol Myers Squibb. GH has received grants from Roche and Bristol Myers Squibb and personal fees from Bristol Myers Squibb, Roche, Amgen, Spectrum and MSD. All the other authors have no conflicts of interest to disclose.

Figures

None
Graphical abstract
Figure 1.
Figure 1.
Trial profile. Qualification for radiotherapy was defined as the presence of bulky disease (maximal tumor diameter ≥7.5 cm) or extralymphatic involvement.
Figure 2.
Figure 2.
Event-free, progression-free, and overall survival according to the therapy arm for patients qualifying for radiotherapy. Graphs show event-free (A), progression-free (B), and overall survival (C) for patients qualifying for radiotherapy treated in radiotherapy-arm or observation-arm and event-free (D), progression-free (E), and overall survival (F) for patients qualifying for radiotherapy treated either with R-CHOP-14 or R-CHOP-21. Hazard ratios for treatment effect adjusted for strata are presented for event-free, progression-free, and overall survival. CI = confidence interval; HR = hazard ratio; PMBCL = primary mediastinal B-cell lymphoma; R-CHOP = rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone.
Figure 3.
Figure 3.
Prognostic factors. Graphs show event-free (A), progression-free (B), and overall survival (C) for patients with primary mediastinal B-cell lymphoma subgroup compared with all other. Hazard ratios for treatment effect adjusted for strata are presented for event-free, progression-free, and overall survival. CI = confidence interval; HR = hazard ratio; PMBCL = primary mediastinal B-cell lymphoma.
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