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Published in: Annals of Hematology 4/2021

Open Access 01-04-2021 | Lymphoma | Original Article

Age-dependent increase of treatment-related mortality in older patients with aggressive B cell lymphoma: analysis of outcome, treatment feasibility, and toxicity in 1171 elderly patients with aggressive B cell lymphoma—data from phase II and III trials of the DSHNHL (German High-Grade Non-Hodgkin’s Lymphoma Study Group)

Authors: Florian Zettl, Marita Ziepert, Bettina Altmann, Samira Zeynalova, Gerhard Held, Viola Pöschel, Karin Hohloch, Gerald G. Wulf, Bertram Glass, Norbert Schmitz, Markus Loeffler, Lorenz Trümper

Published in: Annals of Hematology | Issue 4/2021

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Abstract

In elderly patients (pts) with aggressive B cell lymphoma (aNHL), curative treatment often cannot be administered because of comorbidities and tolerability. We analyzed the influence of age in pts > 60 years receiving the R-CHOP-14 regimen within different prospective DSHNHL trials. Of the RICOVER-60 trial and CHOP-R-ESC trials, 1171 aNHL pts were included in this retrospective analysis of age-dependent event-free survival (EFS), progression-free survival (PFS), and overall survival (OS). All patients received prophylactic G-CSF, and anti-infective prophylaxis with amphotericin B mouth wash and oral fluorchinolone was optional. In the CHOP-R-ESC trials, prophylaxis was augmented to include mandatory continuous orally administered aciclovir and a pneumocystis prophylaxis with cotrimoxazole as well as oral fluorchinolones during neutropenia. The patient population was separated into 4 age groups (61–65 years, 66–70 years, 71–75 years, and 76–80 years). The results from the RICOVER-60 trial were subsequently confirmed in the following CHOP-R-ESC trials by a multivariate analysis adjusted for IPI factors and gender. Significant differences (p < 0.001) in EFS, PFS, and OS were seen between age groups (RICOVER-60). Hematotoxicity, infections, and TRM increased with age. TRM was significantly elevated in the age group 76–80 years. Therefore, this analysis shows that an age above 75 years defines an especially vulnerable patient population when being treated with chemoimmunotherapy for aNHL. Prophylactic anti-infective drugs are essential and clinically effective in reducing morbidity when treating elderly aNHL pts.
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Literature
1.
go back to reference Pfreundschuh M, Kuhnt E, Trumper L, Osterborg A, Trneny M, Shepherd L, Gill DS, Walewski J, Pettengell R, Jaeger U, Zinzani PL, Shpilberg O, Kvaloy S, de Nully Brown P, Stahel R, Milpied N, Lopez-Guillermo A, Poeschel V, Grass S, Loeffler M, Murawski N, MabThera International Trial G (2011) CHOP-like chemotherapy with or without rituximab in young patients with good-prognosis diffuse large-B-cell lymphoma: 6-year results of an open-label randomised study of the MabThera International Trial (MInT) Group. Lancet Oncol 12(11):1013–1022. https://doi.org/10.1016/S1470-2045(11)70235-2CrossRefPubMed Pfreundschuh M, Kuhnt E, Trumper L, Osterborg A, Trneny M, Shepherd L, Gill DS, Walewski J, Pettengell R, Jaeger U, Zinzani PL, Shpilberg O, Kvaloy S, de Nully Brown P, Stahel R, Milpied N, Lopez-Guillermo A, Poeschel V, Grass S, Loeffler M, Murawski N, MabThera International Trial G (2011) CHOP-like chemotherapy with or without rituximab in young patients with good-prognosis diffuse large-B-cell lymphoma: 6-year results of an open-label randomised study of the MabThera International Trial (MInT) Group. Lancet Oncol 12(11):1013–1022. https://​doi.​org/​10.​1016/​S1470-2045(11)70235-2CrossRefPubMed
2.
go back to reference Coiffier B, Lepage E, Briere J, Herbrecht R, Tilly H, Bouabdallah R, Morel P, Van Den Neste E, Salles G, Gaulard P, Reyes F, Lederlin P, Gisselbrecht C (2002) CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 346(4):235–242. https://doi.org/10.1056/NEJMoa011795CrossRefPubMed Coiffier B, Lepage E, Briere J, Herbrecht R, Tilly H, Bouabdallah R, Morel P, Van Den Neste E, Salles G, Gaulard P, Reyes F, Lederlin P, Gisselbrecht C (2002) CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med 346(4):235–242. https://​doi.​org/​10.​1056/​NEJMoa011795CrossRefPubMed
3.
go back to reference Pfreundschuh M, Schubert J, Ziepert M, Schmits R, Mohren M, Lengfelder E, Reiser M, Nickenig C, Clemens M, Peter N, Bokemeyer C, Eimermacher H, Ho A, Hoffmann M, Mertelsmann R, Trumper L, Balleisen L, Liersch R, Metzner B, Hartmann F, Glass B, Poeschel V, Schmitz N, Ruebe C, Feller AC, Loeffler M (2008) Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: a randomised controlled trial (RICOVER-60). Lancet Oncol 9(2):105–116. https://doi.org/10.1016/s1470-2045(08)70002-0CrossRefPubMed Pfreundschuh M, Schubert J, Ziepert M, Schmits R, Mohren M, Lengfelder E, Reiser M, Nickenig C, Clemens M, Peter N, Bokemeyer C, Eimermacher H, Ho A, Hoffmann M, Mertelsmann R, Trumper L, Balleisen L, Liersch R, Metzner B, Hartmann F, Glass B, Poeschel V, Schmitz N, Ruebe C, Feller AC, Loeffler M (2008) Six versus eight cycles of bi-weekly CHOP-14 with or without rituximab in elderly patients with aggressive CD20+ B-cell lymphomas: a randomised controlled trial (RICOVER-60). Lancet Oncol 9(2):105–116. https://​doi.​org/​10.​1016/​s1470-2045(08)70002-0CrossRefPubMed
6.
go back to reference Taplitz RA, Kennedy EB, Bow EJ, Crews J, Gleason C, Hawley DK, Langston AA, Nastoupil LJ, Rajotte M, Rolston K, Strasfeld L, Flowers CR (2018) Outpatient management of fever and neutropenia in adults treated for malignancy: American Society of Clinical Oncology and Infectious Diseases Society of America Clinical Practice Guideline Update. J Clin Oncol 36(14):1443–1453. https://doi.org/10.1200/jco.2017.77.6211CrossRefPubMed Taplitz RA, Kennedy EB, Bow EJ, Crews J, Gleason C, Hawley DK, Langston AA, Nastoupil LJ, Rajotte M, Rolston K, Strasfeld L, Flowers CR (2018) Outpatient management of fever and neutropenia in adults treated for malignancy: American Society of Clinical Oncology and Infectious Diseases Society of America Clinical Practice Guideline Update. J Clin Oncol 36(14):1443–1453. https://​doi.​org/​10.​1200/​jco.​2017.​77.​6211CrossRefPubMed
7.
go back to reference Murawski N, Pfreundschuh M, Zeynalova S, Poeschel V, Hanel M, Held G, Schmitz N, Viardot A, Schmidt C, Hallek M, Witzens-Harig M, Trumper L, Rixecker T, Zwick C (2014) Optimization of rituximab for the treatment of DLBCL (I): dose-dense rituximab in the DENSE-R-CHOP-14 trial of the DSHNHL. Ann Oncol 25(9):1800–1806. https://doi.org/10.1093/annonc/mdu208CrossRefPubMed Murawski N, Pfreundschuh M, Zeynalova S, Poeschel V, Hanel M, Held G, Schmitz N, Viardot A, Schmidt C, Hallek M, Witzens-Harig M, Trumper L, Rixecker T, Zwick C (2014) Optimization of rituximab for the treatment of DLBCL (I): dose-dense rituximab in the DENSE-R-CHOP-14 trial of the DSHNHL. Ann Oncol 25(9):1800–1806. https://​doi.​org/​10.​1093/​annonc/​mdu208CrossRefPubMed
8.
go back to reference Pfreundschuh M, Poeschel V, Zeynalova S, Hanel M, Held G, Schmitz N, Viardot A, Dreyling MH, Hallek M, Mueller C, Wiesen MH, Witzens-Harig M, Truemper L, Keller U, Rixecker T, Zwick C, Murawski N (2014) Optimization of rituximab for the treatment of diffuse large B-cell lymphoma (II): extended rituximab exposure time in the SMARTE-R-CHOP-14 trial of the german high-grade non-Hodgkin lymphoma study group. J Clin Oncol 32(36):4127–4133. https://doi.org/10.1200/jco.2013.54.6861CrossRefPubMed Pfreundschuh M, Poeschel V, Zeynalova S, Hanel M, Held G, Schmitz N, Viardot A, Dreyling MH, Hallek M, Mueller C, Wiesen MH, Witzens-Harig M, Truemper L, Keller U, Rixecker T, Zwick C, Murawski N (2014) Optimization of rituximab for the treatment of diffuse large B-cell lymphoma (II): extended rituximab exposure time in the SMARTE-R-CHOP-14 trial of the german high-grade non-Hodgkin lymphoma study group. J Clin Oncol 32(36):4127–4133. https://​doi.​org/​10.​1200/​jco.​2013.​54.​6861CrossRefPubMed
9.
go back to reference Pfreundschuh M, Murawski N, Zeynalova S, Ziepert M, Loeffler M, Hanel M, Dierlamm J, Keller U, Dreyling M, Truemper L, Frickhofen N, Hunerliturkoglu AN, Schmitz N, Poschel V, Rixecker T, Berdel C, Rube C, Held G, Zwick C (2017) Optimization of rituximab for the treatment of DLBCL: increasing the dose for elderly male patients. Br J Haematol 179(3):410–420. https://doi.org/10.1111/bjh.14860CrossRefPubMed Pfreundschuh M, Murawski N, Zeynalova S, Ziepert M, Loeffler M, Hanel M, Dierlamm J, Keller U, Dreyling M, Truemper L, Frickhofen N, Hunerliturkoglu AN, Schmitz N, Poschel V, Rixecker T, Berdel C, Rube C, Held G, Zwick C (2017) Optimization of rituximab for the treatment of DLBCL: increasing the dose for elderly male patients. Br J Haematol 179(3):410–420. https://​doi.​org/​10.​1111/​bjh.​14860CrossRefPubMed
10.
go back to reference Kaplan EL, Meier P (1958) Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457–481 Kaplan EL, Meier P (1958) Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457–481
11.
go back to reference DuBois DDE (1916) A formula to estimate the approximate surface area if height and weight be known. Arch Intern Med 17:86327 DuBois DDE (1916) A formula to estimate the approximate surface area if height and weight be known. Arch Intern Med 17:86327
12.
go back to reference Wunderlich A, Kloess M, Reiser M, Rudolph C, Truemper L, Bittner S, Schmalenberg H, Schmits R, Pfreundschuh M, Loeffler M, German High-Grade Non-Hodgkin's Lymphoma Study G (2003) Practicability and acute haematological toxicity of 2- and 3-weekly CHOP and CHOEP chemotherapy for aggressive non-Hodgkin’s lymphoma: results from the NHL-B trial of the German High-Grade Non-Hodgkin's Lymphoma Study Group (DSHNHL). Ann Oncol 14(6):881–893CrossRef Wunderlich A, Kloess M, Reiser M, Rudolph C, Truemper L, Bittner S, Schmalenberg H, Schmits R, Pfreundschuh M, Loeffler M, German High-Grade Non-Hodgkin's Lymphoma Study G (2003) Practicability and acute haematological toxicity of 2- and 3-weekly CHOP and CHOEP chemotherapy for aggressive non-Hodgkin’s lymphoma: results from the NHL-B trial of the German High-Grade Non-Hodgkin's Lymphoma Study Group (DSHNHL). Ann Oncol 14(6):881–893CrossRef
15.
go back to reference Tucci A, Martelli M, Rigacci L, Riccomagno P, Cabras MG, Salvi F, Stelitano C, Fabbri A, Storti S, Fogazzi S, Mancuso S, Brugiatelli M, Fama A, Paesano P, Puccini B, Bottelli C, Dalceggio D, Bertagna F, Rossi G, Spina M (2015) Comprehensive geriatric assessment is an essential tool to support treatment decisions in elderly patients with diffuse large B-cell lymphoma: a prospective multicenter evaluation in 173 patients by the Lymphoma Italian Foundation (FIL). Leuk Lymphoma 56(4):921–926. https://doi.org/10.3109/10428194.2014.953142CrossRefPubMed Tucci A, Martelli M, Rigacci L, Riccomagno P, Cabras MG, Salvi F, Stelitano C, Fabbri A, Storti S, Fogazzi S, Mancuso S, Brugiatelli M, Fama A, Paesano P, Puccini B, Bottelli C, Dalceggio D, Bertagna F, Rossi G, Spina M (2015) Comprehensive geriatric assessment is an essential tool to support treatment decisions in elderly patients with diffuse large B-cell lymphoma: a prospective multicenter evaluation in 173 patients by the Lymphoma Italian Foundation (FIL). Leuk Lymphoma 56(4):921–926. https://​doi.​org/​10.​3109/​10428194.​2014.​953142CrossRefPubMed
16.
go back to reference Cunningham D, Hawkes EA, Jack A, Qian W, Smith P, Mouncey P, Pocock C, Ardeshna KM, Radford JA, McMillan A, Davies J, Turner D, Kruger A, Johnson P, Gambell J, Linch D (2013) Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone in patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma: a phase 3 comparison of dose intensification with 14-day versus 21-day cycles. Lancet 381(9880):1817–1826. https://doi.org/10.1016/S0140-6736(13)60313-XCrossRefPubMed Cunningham D, Hawkes EA, Jack A, Qian W, Smith P, Mouncey P, Pocock C, Ardeshna KM, Radford JA, McMillan A, Davies J, Turner D, Kruger A, Johnson P, Gambell J, Linch D (2013) Rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone in patients with newly diagnosed diffuse large B-cell non-Hodgkin lymphoma: a phase 3 comparison of dose intensification with 14-day versus 21-day cycles. Lancet 381(9880):1817–1826. https://​doi.​org/​10.​1016/​S0140-6736(13)60313-XCrossRefPubMed
17.
go back to reference Olszewski AJ, Mantripragada KC, Castillo JJ (2016) Risk factors for early death after rituximab-based immunochemotherapy in older patients with diffuse large B-cell lymphoma. J Natl Compr Cancer Netw 14(9):1121–1129CrossRef Olszewski AJ, Mantripragada KC, Castillo JJ (2016) Risk factors for early death after rituximab-based immunochemotherapy in older patients with diffuse large B-cell lymphoma. J Natl Compr Cancer Netw 14(9):1121–1129CrossRef
18.
go back to reference Peyrade F, Jardin F, Thieblemont C, Thyss A, Emile JF, Castaigne S, Coiffier B, Haioun C, Bologna S, Fitoussi O, Lepeu G, Fruchart C, Bordessoule D, Blanc M, Delarue R, Janvier M, Salles B, Andre M, Fournier M, Gaulard P, Tilly H, Groupe d'Etude des Lymphomes de l'Adulte i (2011) Attenuated immunochemotherapy regimen (R-miniCHOP) in elderly patients older than 80 years with diffuse large B-cell lymphoma: a multicentre, single-arm, phase 2 trial. Lancet Oncol 12(5):460–468. https://doi.org/10.1016/S1470-2045(11)70069-9CrossRefPubMed Peyrade F, Jardin F, Thieblemont C, Thyss A, Emile JF, Castaigne S, Coiffier B, Haioun C, Bologna S, Fitoussi O, Lepeu G, Fruchart C, Bordessoule D, Blanc M, Delarue R, Janvier M, Salles B, Andre M, Fournier M, Gaulard P, Tilly H, Groupe d'Etude des Lymphomes de l'Adulte i (2011) Attenuated immunochemotherapy regimen (R-miniCHOP) in elderly patients older than 80 years with diffuse large B-cell lymphoma: a multicentre, single-arm, phase 2 trial. Lancet Oncol 12(5):460–468. https://​doi.​org/​10.​1016/​S1470-2045(11)70069-9CrossRefPubMed
19.
go back to reference Peyrade F, Bologna S, Delwail V, Emile JF, Pascal L, Ferme C, Schiano JM, Coiffier B, Corront B, Farhat H, Fruchart C, Ghesquieres H, Macro M, Tilly H, Choufi B, Delarue R, Fitoussi O, Gabarre J, Haioun C, Jardin F (2017) Combination of ofatumumab and reduced-dose CHOP for diffuse large B-cell lymphomas in patients aged 80 years or older: an open-label, multicentre, single-arm, phase 2 trial from the LYSA group. Lancet Haematol 4(1):e46–e55. https://doi.org/10.1016/s2352-3026(16)30171-5CrossRefPubMed Peyrade F, Bologna S, Delwail V, Emile JF, Pascal L, Ferme C, Schiano JM, Coiffier B, Corront B, Farhat H, Fruchart C, Ghesquieres H, Macro M, Tilly H, Choufi B, Delarue R, Fitoussi O, Gabarre J, Haioun C, Jardin F (2017) Combination of ofatumumab and reduced-dose CHOP for diffuse large B-cell lymphomas in patients aged 80 years or older: an open-label, multicentre, single-arm, phase 2 trial from the LYSA group. Lancet Haematol 4(1):e46–e55. https://​doi.​org/​10.​1016/​s2352-3026(16)30171-5CrossRefPubMed
21.
go back to reference Zettl F, Braulke F, Ziepert M, Viardot A, Kahl C, Prange-Krex G, Korfel A, Dreyling MH, Illmer T, Birkmann J, Wedding U, Reichert D, Md W, Hartmann F, Hurtz H-J, Schmitz N, Witzens-Harig M, Klapper W, Rosenwald A, Poeschel V, Loeffler M, Wulf G, Altmann B, Truemper L (2019) Rituximab and bendamustine for first-line treatment of frail or elderly patients with aggressive B-cell lymphoma: final results of the prospective phase-II Brenda trial of GLA (German Lymphoma Alliance). Blood 134(Supplement_1):4073CrossRef Zettl F, Braulke F, Ziepert M, Viardot A, Kahl C, Prange-Krex G, Korfel A, Dreyling MH, Illmer T, Birkmann J, Wedding U, Reichert D, Md W, Hartmann F, Hurtz H-J, Schmitz N, Witzens-Harig M, Klapper W, Rosenwald A, Poeschel V, Loeffler M, Wulf G, Altmann B, Truemper L (2019) Rituximab and bendamustine for first-line treatment of frail or elderly patients with aggressive B-cell lymphoma: final results of the prospective phase-II Brenda trial of GLA (German Lymphoma Alliance). Blood 134(Supplement_1):4073CrossRef
Metadata
Title
Age-dependent increase of treatment-related mortality in older patients with aggressive B cell lymphoma: analysis of outcome, treatment feasibility, and toxicity in 1171 elderly patients with aggressive B cell lymphoma—data from phase II and III trials of the DSHNHL (German High-Grade Non-Hodgkin’s Lymphoma Study Group)
Authors
Florian Zettl
Marita Ziepert
Bettina Altmann
Samira Zeynalova
Gerhard Held
Viola Pöschel
Karin Hohloch
Gerald G. Wulf
Bertram Glass
Norbert Schmitz
Markus Loeffler
Lorenz Trümper
Publication date
01-04-2021
Publisher
Springer Berlin Heidelberg
Published in
Annals of Hematology / Issue 4/2021
Print ISSN: 0939-5555
Electronic ISSN: 1432-0584
DOI
https://doi.org/10.1007/s00277-020-04345-3

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