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

Gerhard Held; Lorenz Thurner; Viola Poeschel; German Ott; Christian Schmidt; Konstantinos Christofyllakis; Andreas Viardot; Peter Borchmann; Walburga Engel-Riedel; Norbert Frickhofen; Maike Nickelsen; Ofer Shpilberg; Mathias Witzens-Harig; Frank Griesinger; Beate Krammer-Steiner; Andreas Neubauer; Peter de Nully Brown; Massimo Federico; Bertram Glass; Norbert Schmitz; Gerald Wulf; Lorenz Truemper; Moritz Bewarder; Niels Murawski; Stephan Stilgenbauer; Andreas Rosenwald; Bettina Altmann; Marianne Engelhard; Heinz Schmidberger; Jochen Fleckenstein; Christian Berdel; Markus Loeffler; Marita Ziepert

doi:10.1097/HS9.0000000000000917

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

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

Authors

Gerhard Held¹, Lorenz Thurner², Viola Poeschel², German Ott³, Christian Schmidt⁴, Konstantinos Christofyllakis², Andreas Viardot⁵, Peter Borchmann⁶, Walburga Engel-Riedel⁷, Norbert Frickhofen⁸, Maike Nickelsen⁹, Ofer Shpilberg¹⁰, Mathias Witzens-Harig¹¹, Frank Griesinger¹², Beate Krammer-Steiner¹³, Andreas Neubauer¹⁴, Peter de Nully Brown¹⁵, Massimo Federico¹⁶, Bertram Glass¹⁷, Norbert Schmitz¹⁸, Gerald Wulf¹⁹, Lorenz Truemper¹⁹, Moritz Bewarder², Niels Murawski², Stephan Stilgenbauer², Andreas Rosenwald²⁰, Bettina Altmann²¹, Marianne Engelhard²², Heinz Schmidberger²³, Jochen Fleckenstein²⁴, Christian Berdel²⁴, Markus Loeffler²¹, Marita Ziepert²¹

Affiliations

¹ Department of Internal Medicine 1, Westpfalz-Klinikum, Kaiserslautern, Germany.
² Department of Internal Medicine 1 (Oncology, Hematology, Clinical Immunology and Rheumatology), Saarland University Medical School, Homburg/Saar, Germany.
³ Department of Clinical Pathology, Robert-Bosch-Krankenhaus and Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.
⁴ Department of Medicine III, University Hospital, Munich, Germany.
⁵ Department of Internal Medicine III, University Hospital Ulm, Germany.
⁶ Department of Hematology and Oncology, University Hospital of Cologne, Germany.
⁷ Pulmonary Clinic, Krankenhaus Köln-Merheim, Germany.
⁸ Department of Internal Medicine III, Helios Dr.Horst-Schmidt-Kliniken, Wiesbaden, Germany.
⁹ Oncology Lerchenfeld, Hamburg, Germany.
¹⁰ Department of Hematology, Rabin Medical Center, Beilinson Hospital, Petah-Tiqwa, Israel.
¹¹ Department of Internal Medicine V, University of Heidelberg, Germany.
¹² Department of Internal Oncology, Pius-Hospital, Oldenburg, Germany.
¹³ Department of Internal Medicine, Klinikum Rostock Südstadt, Germany.
¹⁴ Department of Hematology, Oncology and Immunology, University Hospital Marburg, Germany.
¹⁵ Department of Hematology, Rigshospitalet, Copenhagen, Denmark.
¹⁶ CHIMOMO Department, University of Modena and Reggio Emilia, Italy.
¹⁷ Department of Hematology and Stem Cell Transplantation, Helios Klinikum Berlin-Buch, Germany.
¹⁸ Department of Medicine A, Hematology, Oncology and Pneumology, University Hospital Münster, Germany.
¹⁹ Department of Hematology and Oncology, Georg August University of Goettingen, Germany.
²⁰ Institute of Pathology, University of Wuerzburg, and Comprehensive Cancer Center Mainfranken, Germany.
²¹ Institute for Medical Informatics, Statistics and Epidemiology, University Leipzig, Germany.
²² Department of Radiotherapy, University Hospital Essen, Germany.
²³ Department of Radiooncology and Radiotherapy, University Medical Center, Mainz, Germany.
²⁴ Department of Radiotherapy and Radiation Oncology, Saarland University Medical School, Homburg/Saar, Germany.

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%.