Whole-brain radiotherapy or autologous stem-cell transplantation as consolidation strategies after high-dose methotrexate-based chemoimmunotherapy in patients with primary CNS lymphoma: results of the second randomisation of the International Extranodal Lymphoma Study Group-32 phase 2 trial

Andrés J M Ferreri, Kate Cwynarski, Elisa Pulczynski, Christopher P Fox, Elisabeth Schorb, Paul La Rosée, Mascha Binder, Alberto Fabbri, Valter Torri, Eleonora Minacapelli, Monica Falautano, Fiorella Ilariucci, Achille Ambrosetti, Alexander Roth, Claire Hemmaway, Peter Johnson, Kim M Linton, Tobias Pukrop, Jette Sønderskov Gørløv, Monica BalzarottiGeorg Hess, Ulrich Keller, Stephan Stilgenbauer, Jens Panse, Alessandra Tucci, Lorella Orsucci, Francesco Pisani, Alessandro Levis, Stefan W Krause, Hans J Schmoll, Bernd Hertenstein, Mathias Rummel, Jeffery Smith, Michael Pfreundschuh, Giuseppina Cabras, Francesco Angrilli, Maurilio Ponzoni, Martina Deckert, Letterio S Politi, Jürgen Finke, Michele Reni, Franco Cavalli, Emanuele Zucca, Gerald Illerhaus, International Extranodal Lymphoma Study Group (IELSG)

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Abstract

BACKGROUND: The International Extranodal Lymphoma Study Group-32 (IELSG32) trial is an international randomised phase 2 study that addresses two key clinical questions in the treatment of patients with newly diagnosed primary CNS lymphoma. Results of the first randomisation have demonstrated that methotrexate, cytarabine, thiotepa, and rituximab (called the MATRix regimen) is the induction combination associated with significantly better outcome compared with the other induction combinations tested. Here, we report the results of the second randomisation that addresses the efficacy of myeloablative chemotherapy supported by autologous stem-cell transplantation (ASCT), as an alternative to whole-brain radiotherapy (WBRT), as consolidation after high-dose-methotrexate-based chemoimmunotherapy.

METHODS: HIV-negative patients (aged 18-70 years) with newly diagnosed primary CNS lymphoma and an Eastern Cooperative Oncology Group performance status of 0-3 were randomly assigned to receive four courses of methotrexate 3·5 g/m2on day 1 plus cytarabine 2 g/m2twice daily on days 2 and 3 (group A); or the same combination plus two doses of rituximab 375 mg/m2on days -5 and 0 (group B); or the same methotrexate-cytarabine-rituximab combination plus thiotepa 30 mg/m2on day 4 (group C), with the three groups repeating treatment every 3 weeks. Patients with responsive or stable disease after induction treatment, with adequate autologous peripheral blood stem-cell collection, and without persistent iatrogenic side-effects, were eligible for the second randomisation between WBRT (photons of 4-10 MeV; five fractions per week; fraction size 180 cGy; started within 4 weeks from the last induction course; group D) and carmustine-thiotepa conditioned ASCT (carmustine 400 mg/m2on day -6, and thiotepa 5 mg/kg every 12 h on days -5 and -4, followed by reinfusion of autologous peripheral blood stem cells; group E). A permuted block randomised design was adopted for both randomisations, and a computer-generated randomisation list was used within each stratum. No masking after assignment to intervention was adopted. The primary endpoint was 2-year progression-free survival, with induction group and response to induction chemotherapy as stratification parameters. Analyses were done on a modified intention-to-treat basis. This study is registered with ClinicalTrials.gov, number NCT01011920.

FINDINGS: Between Feb 19, 2010, and Aug 27, 2014, 227 patients were recruited from 53 centres in five countries. 219 of 227 enrolled patients were assessable. Of the 122 patients eligible for the second randomisation, 118 patients were randomly assigned to WBRT or ASCT (59 patients per group) and constitute the study population. WBRT and ASCT were both effective, and achieved the predetermined efficacy threshold of at least 40 progression-free survivors at 2 years among the first 52 patients in both groups D and E. There were no significant differences in 2-year progression-free survival between WBRT and ASCT: 80% (95% CI 70-90) in group D and 69% (59-79) in group E (hazard ratio 1·50, 95% CI 0·83-2·71; p=0·17). Both consolidation therapies were well tolerated. Grade 4 non-haematological toxicity was uncommon; as expected, haematological toxicity was more common in patients treated with ASCT than in those who received WBRT. Two toxic deaths (infections) were recorded, both in patients who received ASCT.

INTERPRETATION: WBRT and ASCT are both feasible and effective as consolidation therapies after high-dose methotrexate-based chemoimmunotherapy in patients aged 70 years or younger with primary CNS lymphoma. The risks and implications of cognitive impairment after WBRT should be considered at the time of therapeutic decision.

FUNDING: Agenzia Italiana del Farmaco, Cancer Research UK, Oncosuisse, and Swiss National Science Foundation.

Original languageEnglish
Pages (from-to)e510-e523
JournalThe Lancet Haematology
Volume4
Issue number11
DOIs
Publication statusPublished - Nov 2017

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Stem Cell Transplantation
Random Allocation
Methotrexate
Lymphoma
Radiotherapy
Brain
Thiotepa
Cytarabine
Carmustine
Disease-Free Survival
Therapeutics
Induction Chemotherapy
Poisons
Photons
Survivors
HIV

Keywords

  • Journal Article

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Whole-brain radiotherapy or autologous stem-cell transplantation as consolidation strategies after high-dose methotrexate-based chemoimmunotherapy in patients with primary CNS lymphoma : results of the second randomisation of the International Extranodal Lymphoma Study Group-32 phase 2 trial. / Ferreri, Andrés J M; Cwynarski, Kate; Pulczynski, Elisa; Fox, Christopher P; Schorb, Elisabeth; La Rosée, Paul; Binder, Mascha; Fabbri, Alberto; Torri, Valter; Minacapelli, Eleonora; Falautano, Monica; Ilariucci, Fiorella; Ambrosetti, Achille; Roth, Alexander; Hemmaway, Claire; Johnson, Peter; Linton, Kim M; Pukrop, Tobias; Sønderskov Gørløv, Jette; Balzarotti, Monica; Hess, Georg; Keller, Ulrich; Stilgenbauer, Stephan; Panse, Jens; Tucci, Alessandra; Orsucci, Lorella; Pisani, Francesco; Levis, Alessandro; Krause, Stefan W; Schmoll, Hans J; Hertenstein, Bernd; Rummel, Mathias; Smith, Jeffery; Pfreundschuh, Michael; Cabras, Giuseppina; Angrilli, Francesco; Ponzoni, Maurilio; Deckert, Martina; Politi, Letterio S; Finke, Jürgen; Reni, Michele; Cavalli, Franco; Zucca, Emanuele; Illerhaus, Gerald; International Extranodal Lymphoma Study Group (IELSG).

In: The Lancet Haematology, Vol. 4, No. 11, 11.2017, p. e510-e523.

Research output: Contribution to journalArticle

Ferreri, AJM, Cwynarski, K, Pulczynski, E, Fox, CP, Schorb, E, La Rosée, P, Binder, M, Fabbri, A, Torri, V, Minacapelli, E, Falautano, M, Ilariucci, F, Ambrosetti, A, Roth, A, Hemmaway, C, Johnson, P, Linton, KM, Pukrop, T, Sønderskov Gørløv, J, Balzarotti, M, Hess, G, Keller, U, Stilgenbauer, S, Panse, J, Tucci, A, Orsucci, L, Pisani, F, Levis, A, Krause, SW, Schmoll, HJ, Hertenstein, B, Rummel, M, Smith, J, Pfreundschuh, M, Cabras, G, Angrilli, F, Ponzoni, M, Deckert, M, Politi, LS, Finke, J, Reni, M, Cavalli, F, Zucca, E, Illerhaus, G & International Extranodal Lymphoma Study Group (IELSG) 2017, 'Whole-brain radiotherapy or autologous stem-cell transplantation as consolidation strategies after high-dose methotrexate-based chemoimmunotherapy in patients with primary CNS lymphoma: results of the second randomisation of the International Extranodal Lymphoma Study Group-32 phase 2 trial', The Lancet Haematology, vol. 4, no. 11, pp. e510-e523. https://doi.org/10.1016/S2352-3026(17)30174-6
Ferreri, Andrés J M ; Cwynarski, Kate ; Pulczynski, Elisa ; Fox, Christopher P ; Schorb, Elisabeth ; La Rosée, Paul ; Binder, Mascha ; Fabbri, Alberto ; Torri, Valter ; Minacapelli, Eleonora ; Falautano, Monica ; Ilariucci, Fiorella ; Ambrosetti, Achille ; Roth, Alexander ; Hemmaway, Claire ; Johnson, Peter ; Linton, Kim M ; Pukrop, Tobias ; Sønderskov Gørløv, Jette ; Balzarotti, Monica ; Hess, Georg ; Keller, Ulrich ; Stilgenbauer, Stephan ; Panse, Jens ; Tucci, Alessandra ; Orsucci, Lorella ; Pisani, Francesco ; Levis, Alessandro ; Krause, Stefan W ; Schmoll, Hans J ; Hertenstein, Bernd ; Rummel, Mathias ; Smith, Jeffery ; Pfreundschuh, Michael ; Cabras, Giuseppina ; Angrilli, Francesco ; Ponzoni, Maurilio ; Deckert, Martina ; Politi, Letterio S ; Finke, Jürgen ; Reni, Michele ; Cavalli, Franco ; Zucca, Emanuele ; Illerhaus, Gerald ; International Extranodal Lymphoma Study Group (IELSG). / Whole-brain radiotherapy or autologous stem-cell transplantation as consolidation strategies after high-dose methotrexate-based chemoimmunotherapy in patients with primary CNS lymphoma : results of the second randomisation of the International Extranodal Lymphoma Study Group-32 phase 2 trial. In: The Lancet Haematology. 2017 ; Vol. 4, No. 11. pp. e510-e523.
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abstract = "BACKGROUND: The International Extranodal Lymphoma Study Group-32 (IELSG32) trial is an international randomised phase 2 study that addresses two key clinical questions in the treatment of patients with newly diagnosed primary CNS lymphoma. Results of the first randomisation have demonstrated that methotrexate, cytarabine, thiotepa, and rituximab (called the MATRix regimen) is the induction combination associated with significantly better outcome compared with the other induction combinations tested. Here, we report the results of the second randomisation that addresses the efficacy of myeloablative chemotherapy supported by autologous stem-cell transplantation (ASCT), as an alternative to whole-brain radiotherapy (WBRT), as consolidation after high-dose-methotrexate-based chemoimmunotherapy.METHODS: HIV-negative patients (aged 18-70 years) with newly diagnosed primary CNS lymphoma and an Eastern Cooperative Oncology Group performance status of 0-3 were randomly assigned to receive four courses of methotrexate 3·5 g/m2on day 1 plus cytarabine 2 g/m2twice daily on days 2 and 3 (group A); or the same combination plus two doses of rituximab 375 mg/m2on days -5 and 0 (group B); or the same methotrexate-cytarabine-rituximab combination plus thiotepa 30 mg/m2on day 4 (group C), with the three groups repeating treatment every 3 weeks. Patients with responsive or stable disease after induction treatment, with adequate autologous peripheral blood stem-cell collection, and without persistent iatrogenic side-effects, were eligible for the second randomisation between WBRT (photons of 4-10 MeV; five fractions per week; fraction size 180 cGy; started within 4 weeks from the last induction course; group D) and carmustine-thiotepa conditioned ASCT (carmustine 400 mg/m2on day -6, and thiotepa 5 mg/kg every 12 h on days -5 and -4, followed by reinfusion of autologous peripheral blood stem cells; group E). A permuted block randomised design was adopted for both randomisations, and a computer-generated randomisation list was used within each stratum. No masking after assignment to intervention was adopted. The primary endpoint was 2-year progression-free survival, with induction group and response to induction chemotherapy as stratification parameters. Analyses were done on a modified intention-to-treat basis. This study is registered with ClinicalTrials.gov, number NCT01011920.FINDINGS: Between Feb 19, 2010, and Aug 27, 2014, 227 patients were recruited from 53 centres in five countries. 219 of 227 enrolled patients were assessable. Of the 122 patients eligible for the second randomisation, 118 patients were randomly assigned to WBRT or ASCT (59 patients per group) and constitute the study population. WBRT and ASCT were both effective, and achieved the predetermined efficacy threshold of at least 40 progression-free survivors at 2 years among the first 52 patients in both groups D and E. There were no significant differences in 2-year progression-free survival between WBRT and ASCT: 80{\%} (95{\%} CI 70-90) in group D and 69{\%} (59-79) in group E (hazard ratio 1·50, 95{\%} CI 0·83-2·71; p=0·17). Both consolidation therapies were well tolerated. Grade 4 non-haematological toxicity was uncommon; as expected, haematological toxicity was more common in patients treated with ASCT than in those who received WBRT. Two toxic deaths (infections) were recorded, both in patients who received ASCT.INTERPRETATION: WBRT and ASCT are both feasible and effective as consolidation therapies after high-dose methotrexate-based chemoimmunotherapy in patients aged 70 years or younger with primary CNS lymphoma. The risks and implications of cognitive impairment after WBRT should be considered at the time of therapeutic decision.FUNDING: Agenzia Italiana del Farmaco, Cancer Research UK, Oncosuisse, and Swiss National Science Foundation.",
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author = "Ferreri, {Andr{\'e}s J M} and Kate Cwynarski and Elisa Pulczynski and Fox, {Christopher P} and Elisabeth Schorb and {La Ros{\'e}e}, Paul and Mascha Binder and Alberto Fabbri and Valter Torri and Eleonora Minacapelli and Monica Falautano and Fiorella Ilariucci and Achille Ambrosetti and Alexander Roth and Claire Hemmaway and Peter Johnson and Linton, {Kim M} and Tobias Pukrop and {S{\o}nderskov G{\o}rl{\o}v}, Jette and Monica Balzarotti and Georg Hess and Ulrich Keller and Stephan Stilgenbauer and Jens Panse and Alessandra Tucci and Lorella Orsucci and Francesco Pisani and Alessandro Levis and Krause, {Stefan W} and Schmoll, {Hans J} and Bernd Hertenstein and Mathias Rummel and Jeffery Smith and Michael Pfreundschuh and Giuseppina Cabras and Francesco Angrilli and Maurilio Ponzoni and Martina Deckert and Politi, {Letterio S} and J{\"u}rgen Finke and Michele Reni and Franco Cavalli and Emanuele Zucca and Gerald Illerhaus and {International Extranodal Lymphoma Study Group (IELSG)}",
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year = "2017",
month = "11",
doi = "10.1016/S2352-3026(17)30174-6",
language = "English",
volume = "4",
pages = "e510--e523",
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TY - JOUR

T1 - Whole-brain radiotherapy or autologous stem-cell transplantation as consolidation strategies after high-dose methotrexate-based chemoimmunotherapy in patients with primary CNS lymphoma

T2 - results of the second randomisation of the International Extranodal Lymphoma Study Group-32 phase 2 trial

AU - Ferreri, Andrés J M

AU - Cwynarski, Kate

AU - Pulczynski, Elisa

AU - Fox, Christopher P

AU - Schorb, Elisabeth

AU - La Rosée, Paul

AU - Binder, Mascha

AU - Fabbri, Alberto

AU - Torri, Valter

AU - Minacapelli, Eleonora

AU - Falautano, Monica

AU - Ilariucci, Fiorella

AU - Ambrosetti, Achille

AU - Roth, Alexander

AU - Hemmaway, Claire

AU - Johnson, Peter

AU - Linton, Kim M

AU - Pukrop, Tobias

AU - Sønderskov Gørløv, Jette

AU - Balzarotti, Monica

AU - Hess, Georg

AU - Keller, Ulrich

AU - Stilgenbauer, Stephan

AU - Panse, Jens

AU - Tucci, Alessandra

AU - Orsucci, Lorella

AU - Pisani, Francesco

AU - Levis, Alessandro

AU - Krause, Stefan W

AU - Schmoll, Hans J

AU - Hertenstein, Bernd

AU - Rummel, Mathias

AU - Smith, Jeffery

AU - Pfreundschuh, Michael

AU - Cabras, Giuseppina

AU - Angrilli, Francesco

AU - Ponzoni, Maurilio

AU - Deckert, Martina

AU - Politi, Letterio S

AU - Finke, Jürgen

AU - Reni, Michele

AU - Cavalli, Franco

AU - Zucca, Emanuele

AU - Illerhaus, Gerald

AU - International Extranodal Lymphoma Study Group (IELSG)

N1 - Copyright © 2017 Elsevier Ltd. All rights reserved.

PY - 2017/11

Y1 - 2017/11

N2 - BACKGROUND: The International Extranodal Lymphoma Study Group-32 (IELSG32) trial is an international randomised phase 2 study that addresses two key clinical questions in the treatment of patients with newly diagnosed primary CNS lymphoma. Results of the first randomisation have demonstrated that methotrexate, cytarabine, thiotepa, and rituximab (called the MATRix regimen) is the induction combination associated with significantly better outcome compared with the other induction combinations tested. Here, we report the results of the second randomisation that addresses the efficacy of myeloablative chemotherapy supported by autologous stem-cell transplantation (ASCT), as an alternative to whole-brain radiotherapy (WBRT), as consolidation after high-dose-methotrexate-based chemoimmunotherapy.METHODS: HIV-negative patients (aged 18-70 years) with newly diagnosed primary CNS lymphoma and an Eastern Cooperative Oncology Group performance status of 0-3 were randomly assigned to receive four courses of methotrexate 3·5 g/m2on day 1 plus cytarabine 2 g/m2twice daily on days 2 and 3 (group A); or the same combination plus two doses of rituximab 375 mg/m2on days -5 and 0 (group B); or the same methotrexate-cytarabine-rituximab combination plus thiotepa 30 mg/m2on day 4 (group C), with the three groups repeating treatment every 3 weeks. Patients with responsive or stable disease after induction treatment, with adequate autologous peripheral blood stem-cell collection, and without persistent iatrogenic side-effects, were eligible for the second randomisation between WBRT (photons of 4-10 MeV; five fractions per week; fraction size 180 cGy; started within 4 weeks from the last induction course; group D) and carmustine-thiotepa conditioned ASCT (carmustine 400 mg/m2on day -6, and thiotepa 5 mg/kg every 12 h on days -5 and -4, followed by reinfusion of autologous peripheral blood stem cells; group E). A permuted block randomised design was adopted for both randomisations, and a computer-generated randomisation list was used within each stratum. No masking after assignment to intervention was adopted. The primary endpoint was 2-year progression-free survival, with induction group and response to induction chemotherapy as stratification parameters. Analyses were done on a modified intention-to-treat basis. This study is registered with ClinicalTrials.gov, number NCT01011920.FINDINGS: Between Feb 19, 2010, and Aug 27, 2014, 227 patients were recruited from 53 centres in five countries. 219 of 227 enrolled patients were assessable. Of the 122 patients eligible for the second randomisation, 118 patients were randomly assigned to WBRT or ASCT (59 patients per group) and constitute the study population. WBRT and ASCT were both effective, and achieved the predetermined efficacy threshold of at least 40 progression-free survivors at 2 years among the first 52 patients in both groups D and E. There were no significant differences in 2-year progression-free survival between WBRT and ASCT: 80% (95% CI 70-90) in group D and 69% (59-79) in group E (hazard ratio 1·50, 95% CI 0·83-2·71; p=0·17). Both consolidation therapies were well tolerated. Grade 4 non-haematological toxicity was uncommon; as expected, haematological toxicity was more common in patients treated with ASCT than in those who received WBRT. Two toxic deaths (infections) were recorded, both in patients who received ASCT.INTERPRETATION: WBRT and ASCT are both feasible and effective as consolidation therapies after high-dose methotrexate-based chemoimmunotherapy in patients aged 70 years or younger with primary CNS lymphoma. The risks and implications of cognitive impairment after WBRT should be considered at the time of therapeutic decision.FUNDING: Agenzia Italiana del Farmaco, Cancer Research UK, Oncosuisse, and Swiss National Science Foundation.

AB - BACKGROUND: The International Extranodal Lymphoma Study Group-32 (IELSG32) trial is an international randomised phase 2 study that addresses two key clinical questions in the treatment of patients with newly diagnosed primary CNS lymphoma. Results of the first randomisation have demonstrated that methotrexate, cytarabine, thiotepa, and rituximab (called the MATRix regimen) is the induction combination associated with significantly better outcome compared with the other induction combinations tested. Here, we report the results of the second randomisation that addresses the efficacy of myeloablative chemotherapy supported by autologous stem-cell transplantation (ASCT), as an alternative to whole-brain radiotherapy (WBRT), as consolidation after high-dose-methotrexate-based chemoimmunotherapy.METHODS: HIV-negative patients (aged 18-70 years) with newly diagnosed primary CNS lymphoma and an Eastern Cooperative Oncology Group performance status of 0-3 were randomly assigned to receive four courses of methotrexate 3·5 g/m2on day 1 plus cytarabine 2 g/m2twice daily on days 2 and 3 (group A); or the same combination plus two doses of rituximab 375 mg/m2on days -5 and 0 (group B); or the same methotrexate-cytarabine-rituximab combination plus thiotepa 30 mg/m2on day 4 (group C), with the three groups repeating treatment every 3 weeks. Patients with responsive or stable disease after induction treatment, with adequate autologous peripheral blood stem-cell collection, and without persistent iatrogenic side-effects, were eligible for the second randomisation between WBRT (photons of 4-10 MeV; five fractions per week; fraction size 180 cGy; started within 4 weeks from the last induction course; group D) and carmustine-thiotepa conditioned ASCT (carmustine 400 mg/m2on day -6, and thiotepa 5 mg/kg every 12 h on days -5 and -4, followed by reinfusion of autologous peripheral blood stem cells; group E). A permuted block randomised design was adopted for both randomisations, and a computer-generated randomisation list was used within each stratum. No masking after assignment to intervention was adopted. The primary endpoint was 2-year progression-free survival, with induction group and response to induction chemotherapy as stratification parameters. Analyses were done on a modified intention-to-treat basis. This study is registered with ClinicalTrials.gov, number NCT01011920.FINDINGS: Between Feb 19, 2010, and Aug 27, 2014, 227 patients were recruited from 53 centres in five countries. 219 of 227 enrolled patients were assessable. Of the 122 patients eligible for the second randomisation, 118 patients were randomly assigned to WBRT or ASCT (59 patients per group) and constitute the study population. WBRT and ASCT were both effective, and achieved the predetermined efficacy threshold of at least 40 progression-free survivors at 2 years among the first 52 patients in both groups D and E. There were no significant differences in 2-year progression-free survival between WBRT and ASCT: 80% (95% CI 70-90) in group D and 69% (59-79) in group E (hazard ratio 1·50, 95% CI 0·83-2·71; p=0·17). Both consolidation therapies were well tolerated. Grade 4 non-haematological toxicity was uncommon; as expected, haematological toxicity was more common in patients treated with ASCT than in those who received WBRT. Two toxic deaths (infections) were recorded, both in patients who received ASCT.INTERPRETATION: WBRT and ASCT are both feasible and effective as consolidation therapies after high-dose methotrexate-based chemoimmunotherapy in patients aged 70 years or younger with primary CNS lymphoma. The risks and implications of cognitive impairment after WBRT should be considered at the time of therapeutic decision.FUNDING: Agenzia Italiana del Farmaco, Cancer Research UK, Oncosuisse, and Swiss National Science Foundation.

KW - Journal Article

U2 - 10.1016/S2352-3026(17)30174-6

DO - 10.1016/S2352-3026(17)30174-6

M3 - Article

C2 - 29054815

VL - 4

SP - e510-e523

JO - The Lancet Haematology

JF - The Lancet Haematology

SN - 2352-3026

IS - 11

ER -