MATRIX FOLLOWED BY AUTOLOGOUS TRANSPLANT IS ASSOCIATED WITH EXCELLENT SURVIVAL AND NEUROTOLERABILITY IN PRIMARY CNS LYMPHOMA: RESULTS OF THE IELSG32 TRIAL AT A MEDIAN FOLLOW-UP OF 88 MONTHS
Author(s): ,
Gerald Illerhaus
Affiliations:
Klinikum der Landeshauptstadt Stuttgart gKAöR
,

Affiliations:
Standort Mitte, Katharinenhospital,Klinik für Hämatologie, Onkologie und Palliativmedizin,Stuttgart,Germany
,
Kate Cwynarski
Affiliations:
Department of Haematology UCLH, Informazioni di sicurezza sul COVID-19 University College London Hospitals NHS Foundation Trust,lLondon,United Kingdom
,
Elisa Pulczynski
Affiliations:
Department of Haematology,Aarhus University Hospital,Aarhus,Denmark
,
Christopher Fox
Affiliations:
Clinical Haematology City Campus,Nottingham University Hospitals NHS Trust,Nottingham,United Kingdom
,
Elisabeth Schorb
Affiliations:
Klinik für INnere Medizin I,Universitätsklinikum Freiburg,Freiburg,Germany
,
Claudia Celico
Affiliations:
Unità di Neuroriabilitazione,IRCCS San Raffaele Scientific Institute,Milan,Italy
,
Monica Falautano
Affiliations:
Institute of Experimental Neurology,IRCCS San Raffaele Scientific Institute,Milan,Italy
,
Alessandro Nonis
Affiliations:
University Centre for Statistics in the Biomedical Sciences,IRCCS San Raffaele Scientific Institute,Milan,Italy
,
Paul La Rosée
Affiliations:
Klinik für Innere Medizin II,Schwarzwald-Baar Klinikum,VILLINGEN-SCHWENNINGEN,Germany
,
Mascha Binder
Affiliations:
Zentrum für Onkologie,Universitätskrankenhaus Hamburg-Eppendorf - UKE,Hamburg,Germany
,
Alberto Fabbri
Affiliations:
UOC Ematologia e trapianti,Azienda ospedaliera universitaria senese,Siena,Italy
,
Fiorella Ilariucci
Affiliations:
Arcispedale Santa Maria Nuova,Azienda Ospedaliera di Reggio Emilia,Reggio Emilia,Italy
,
Mauro Krampera
Affiliations:
Divisione di ematologia,Policlinico G.B. Rossi,Verona,Italy
,
Alexander Röth
Affiliations:
Klinik für Hämatologie und Stammzelltransplantation,Universitätsmedizin Essen (AöR),Essen,Germany
,
Claire Hemmaway
Affiliations:
Queen's Hospital,Romford,United Kingdom
,
Peter W M Johnson
Affiliations:
UK NCRI Lymphoma Group,Southampton General Hospital,Southampton,United Kingdom
,
Kim Linton
Affiliations:
Manchester Cancer Research Centre,University of Manchester,Manchester,United Kingdom
,
Tobias Pukrop
Affiliations:
Universitätsklinikum Regensburg,Regensburg,Germany
,
Jette Sønderskov Gørløv
Affiliations:
Department of Hematology,Rigshospitalet,Copenhagen,Denmark
,
Monica Balzarrotti
Affiliations:
Hematology,Humanitas Research Hospital,Rozzano,Italy
,
Georg Hess
Affiliations:
III. Medizinische Klinik und Poliklinik,Universitätsmedizin Mainz,Mainz,Germany
,
Ulrich Keller
Affiliations:
III. Medizinischen Klinik des Klinikums rechts der Isar,Technische Universität München,München,Germany
,
Stephan Stilgenbauer
Affiliations:
Klinik für Innere Medizin,Universitätsklinikum Ulm,Ulm,Germany
,
Jens Panse
Affiliations:
Klinik für Innere Medizin IV,Universitätsklinikum Aachen,Aachen,Germany
,
Alessandra Tucci
Affiliations:
USD Sezione Ematologia,Spedali Civili,Brescia,Italy
,
Lorella Orsucci
Affiliations:
Ematologia,AOU Città della Salute e della Scienza di Torino,Torino,Italy
,
Francesco Pisani
Affiliations:
S.C. Ematologia,Istituto Regina Elena,Roma,Italy
,
Manuela Zanni
Affiliations:
SC Ematologia,AO Santi Antonio e Biagio e Cesare Arrigo,Alessandria,Italy
,
Stefan Krause
Affiliations:
Medizinische Klinik 5,Universitätsklinikum Erlangen,Erlangen,Germany
,
Hans Joachim Schmoll
Affiliations:
Klinik für Hämatologie/Onkologie,Martin-Luther Universität,Halle,Germany
,
Bernd Hertenstein
Affiliations:
Medizinische Klinik I,Klinikum Bremen-Mitte GmbH,Bremen,Germany
,
Mathias Rummel
Affiliations:
Medizinische Klinik IV,Klinikum der Justus-Liebing-Universität,Giessen,Germany
,
Jeffery Smith
Affiliations:
Haematology,University Hospital Aintree,Liverpool,United Kingdom
,
Lorenz Thurner
Affiliations:
Innere Medizin I,Universitätsklinikum des Saarlandes,Homburg,Germany
,
Maria Giuseppina Cabras
Affiliations:
Unità Operativa di Ematologia,Ospedale A. Businco,Cagliari,Italy
,
Elsa Pennese
Affiliations:
Centro diagnosi e terapia dei linfomi,Presidio Ospedaliero Spirito Santo,Pescara,Italy
,
Maurilio Ponzoni
Affiliations:
Haematopathology Diagnostic Area,IRCCS San Raffaele Scientific Institute,Milano,Italy
,
Martina Deckert
Affiliations:
Department of Neuropathology,University of Cologne,Cologne,Germany
,
Letterio Politi
Affiliations:
Neuroradiology research,IRCCS San Raffaele Scientific Institute,Milano,Italy
,
Jürgen Finke
Affiliations:
Klinik für Innere Medizin I,Universitätsklinikum Freiburg,Freiburg,Germany
,
Antonella Ferranti
Affiliations:
Fondazione Italiana Linfomi,Alessandria,Italy
,
Kelly Cozens
Affiliations:
Clinical Trials Unit,University of Southampton,Southampton,United Kingdom
,
Elvira Burger
Affiliations:
Projektkoordination Klinische Studien,Universitätsklinikum Freiburg,Freiburg,Germany
,
Nicoletta Ielmini
Affiliations:
International Extranodal Lymphoma Study Group,Foundation for the Institute of Oncology Research,Bellinzona,Switzerland
,
Franco Cavalli
Affiliations:
International Extranodal Lymphoma Study Group,Foundation for the Institute of Oncology Research,Bellinzona,Switzerland
,
Emanuele Zucca
Affiliations:
International Extranodal Lymphoma Study Group,Foundation for the Institute of Oncology Research,Bellinzona,Switzerland
Andrés J.M. Ferreri
Affiliations:
Unità Operativa di Oncologia Medica,IRCCS San Raffaele Scientific Institute,Milano,Italy
EHA Library. Illerhaus G. 06/09/21; 324627; S219
Gerald Illerhaus
Gerald Illerhaus
Contributions
Abstract
Presentation during EHA2021: All Oral presentations will be made available as of Friday, June 11, 2021 (09:00 CEST) and will be accessible for on-demand viewing until August 15, 2021 on the Virtual Congress platform.

Abstract: S219

Type: Oral Presentation

Session title: Aggressive lymphoma - CAR-T & transplant

Background
The IELSG32 trial has shown the significantly better activity and acceptable safety profile of MATRIX regimen and a similar efficacy of consolidation with whole-brain irradiation (WBRT) or autologous transplantation (ASCT) in pts ≤70 yo with primary CNS lymphoma (PCNSL). However, events after a more extended follow-up remain to be addressed.

Aims
To establish the associations among different treatment arms of the IELSG32 trial and OS, late toxicity, incidence of secondary tumors, and cognitive impairment at a median follow-up of 88 (IQR 77-99) months.

Methods

HIV-neg pts 18-70 yo with ECOG PS ≤3 (PS ≤2 if 66-70 yo) with untreated PCNSL were randomly assigned to receive 4 courses of methotrexate-cytarabine (arm A), or arm A plus rituximab (arm B), or arm B plus thiotepa (arm C; MATRIX). Pts with responsive/stable disease were further randomized between WBRT (arm D) and BCNU-thiotepa/ASCT (arm E). Primary endpoints were CRR (1st random) and PFS (2nd random). Effects of treatment on cognitive functions and quality of life (QoL) were addressed comparing results of the IPCG tests panel and EORTC-QLQ performed immediately after treatment and at the last follow-up visit.

Results

219 assessable pts (median age 58; range 18-70) were randomized (arm A 75; B 69; C 75). After induction, 167 (76%) pts had responsive or stable disease; 118 (71%) of them were further randomized (arm D 59; E 59), whereas 49 pts were excluded (poor mobilizers, poor conditions, patients’ refusal).


15 (7%) pts died of toxicity during treatment. 87 (40%) pts remain relapse-free (A 17; B 28; C 42); 14 of them died of infections (n=4), sudden death (4), cognitive decline (3), second tumor (2), and car accident (1). 117 (53%) pts experienced relapse: 96 died of lymphoma, 14 achieved tumor remission upon salvage therapy and remained relapse-free at 39-121 months, while 7 died of complications during salvage therapy. Second cancers were diagnosed in 8 (4%) pts after 48-96 months from WBRT (5) or ASCT (3); two of them were lethal, the other six remained relapse-free after surgical resection. Deaths in relapse-free pts, deaths occurred during salvage treatment and secondary tumors were not significantly related to induction or consolidation treatments (Table).


Neuropsychological tests showed a statistically significant impairment in some attentive and executive functions in pts treated with WBRT, while a significant improvement was noted in these functions as well as in memory and QoL in transplanted pts.


Pts treated with MATRIX (arm C) showed a significantly better PFS, with a 7-yr PFS of 20±5% for arm A, 29±6% for arm B and 52±6% for arm C (A vs C p=0.00002; B vs C p=0.01). PFS was similar in both consolidation arms (7-yr: 55±7% and 50±7%; p=0.35). 87 pts are alive (arm A 18; B 27; C 42), with a 7-yr OS of 26±5%, 37±6% and 56±6%, respectively (A vs C p=0.00007; B vs C p=0.03). OS was similar in both consolidation arms (7-yr: 63±6% and 57±6%, p=0.17). Pts treated with MATRIX and consolidation had a 7-yr OS of 70±6%, without a difference between WBRT and ASCT. In multivariable analysis, IELSG score, number of lesions and induction arm were associated with OS; gender, CSF cytology and consolidation were not.

Conclusion

MATRIX regimen was associated with excellent long-lasting survival in PCNSL pts ≤70 ys. WBRT and ASCT exhibit similar efficacy. In comparison with the other therapeutic arms, MATRIX and ASCT were not associated with higher non-relapse mortality and incidence of second tumors, whereas impairment of specific cognitive functions after WBRT was confirmed.

Keyword(s): Autologous hematopoietic stem cell transplantation, CNS lymphoma, Radiotherapy

Presentation during EHA2021: All Oral presentations will be made available as of Friday, June 11, 2021 (09:00 CEST) and will be accessible for on-demand viewing until August 15, 2021 on the Virtual Congress platform.

Abstract: S219

Type: Oral Presentation

Session title: Aggressive lymphoma - CAR-T & transplant

Background
The IELSG32 trial has shown the significantly better activity and acceptable safety profile of MATRIX regimen and a similar efficacy of consolidation with whole-brain irradiation (WBRT) or autologous transplantation (ASCT) in pts ≤70 yo with primary CNS lymphoma (PCNSL). However, events after a more extended follow-up remain to be addressed.

Aims
To establish the associations among different treatment arms of the IELSG32 trial and OS, late toxicity, incidence of secondary tumors, and cognitive impairment at a median follow-up of 88 (IQR 77-99) months.

Methods

HIV-neg pts 18-70 yo with ECOG PS ≤3 (PS ≤2 if 66-70 yo) with untreated PCNSL were randomly assigned to receive 4 courses of methotrexate-cytarabine (arm A), or arm A plus rituximab (arm B), or arm B plus thiotepa (arm C; MATRIX). Pts with responsive/stable disease were further randomized between WBRT (arm D) and BCNU-thiotepa/ASCT (arm E). Primary endpoints were CRR (1st random) and PFS (2nd random). Effects of treatment on cognitive functions and quality of life (QoL) were addressed comparing results of the IPCG tests panel and EORTC-QLQ performed immediately after treatment and at the last follow-up visit.

Results

219 assessable pts (median age 58; range 18-70) were randomized (arm A 75; B 69; C 75). After induction, 167 (76%) pts had responsive or stable disease; 118 (71%) of them were further randomized (arm D 59; E 59), whereas 49 pts were excluded (poor mobilizers, poor conditions, patients’ refusal).


15 (7%) pts died of toxicity during treatment. 87 (40%) pts remain relapse-free (A 17; B 28; C 42); 14 of them died of infections (n=4), sudden death (4), cognitive decline (3), second tumor (2), and car accident (1). 117 (53%) pts experienced relapse: 96 died of lymphoma, 14 achieved tumor remission upon salvage therapy and remained relapse-free at 39-121 months, while 7 died of complications during salvage therapy. Second cancers were diagnosed in 8 (4%) pts after 48-96 months from WBRT (5) or ASCT (3); two of them were lethal, the other six remained relapse-free after surgical resection. Deaths in relapse-free pts, deaths occurred during salvage treatment and secondary tumors were not significantly related to induction or consolidation treatments (Table).


Neuropsychological tests showed a statistically significant impairment in some attentive and executive functions in pts treated with WBRT, while a significant improvement was noted in these functions as well as in memory and QoL in transplanted pts.


Pts treated with MATRIX (arm C) showed a significantly better PFS, with a 7-yr PFS of 20±5% for arm A, 29±6% for arm B and 52±6% for arm C (A vs C p=0.00002; B vs C p=0.01). PFS was similar in both consolidation arms (7-yr: 55±7% and 50±7%; p=0.35). 87 pts are alive (arm A 18; B 27; C 42), with a 7-yr OS of 26±5%, 37±6% and 56±6%, respectively (A vs C p=0.00007; B vs C p=0.03). OS was similar in both consolidation arms (7-yr: 63±6% and 57±6%, p=0.17). Pts treated with MATRIX and consolidation had a 7-yr OS of 70±6%, without a difference between WBRT and ASCT. In multivariable analysis, IELSG score, number of lesions and induction arm were associated with OS; gender, CSF cytology and consolidation were not.

Conclusion

MATRIX regimen was associated with excellent long-lasting survival in PCNSL pts ≤70 ys. WBRT and ASCT exhibit similar efficacy. In comparison with the other therapeutic arms, MATRIX and ASCT were not associated with higher non-relapse mortality and incidence of second tumors, whereas impairment of specific cognitive functions after WBRT was confirmed.

Keyword(s): Autologous hematopoietic stem cell transplantation, CNS lymphoma, Radiotherapy

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