Gerald Illerhaus1, Benjamin Kasenda2, Gabriele Ihorst3, Gerlinde Egerer4, Monika Lamprecht5, Ulrich Keller6, Hans-Heinrich Wolf7, Carsten Hirt8, Stephan Stilgenbauer9, Mascha Binder10, Peter Hau11, Matthias Edinger12, Norbert Frickhofen13, Martin Bentz14, Robert Möhle15, Alexander Röth16, Michael Pfreundschuh17, Louisa von Baumgarten18, Martina Deckert19, Claudia Hader20, Heidi Fricker21, Elke Valk22, Elisabeth Schorb21, Kristina Fritsch21, Jürgen Finke21. 1. Department of Haematology/Oncology and Palliative Care, Klinikum Stuttgart, Stuttgart, Germany; Department of Hematology, Oncology, and Stem-Cell Transplantation, University Medical Hospital and Faculty of Medicine, Albert-Ludwigs University, Freiburg, Germany. Electronic address: g.illerhaus@klinikum-stuttgart.de. 2. Department of Haematology/Oncology and Palliative Care, Klinikum Stuttgart, Stuttgart, Germany; Department of Medicine, Royal Marsden Hospital, London, UK. 3. Clinical Trials Unit, University of Freiburg Medical Centre, Freiburg, Germany. 4. Department of Haematology and Oncology, Heidelberg University, Heidelberg, Germany. 5. Department of Internal Medicine II, University Hospital of Schleswig-Holstein, Kiel, Germany. 6. III Medical Department, Technische Universität München, Munich, Germany. 7. Department of Haematology and Oncology, University Hospital Halle, Halle, Germany. 8. Hematology and Oncology, Clinic for Internal Medicine C, University of Greifswald, Greifswald, Germany. 9. Department of Internal Medicine III, University of Ulm, Ulm, Germany. 10. Department of Internal Medicine II, Oncology, Hematology, and Bone Marrow Transplantation with section of Pneumology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 11. Department of Neurology and Wilhelm Sander-NeuroOncology Unit, University Hospital Regensburg, Regensburg, Germany. 12. Department of Medicine, University Hospital Regensburg, Regensburg, Germany. 13. Department of Haematology and Oncology, HELIOS Dr Horst Schmidt Kliniken, Wiesbaden, Germany. 14. Medizinische Klinik, Städtisches Klinikum Karlsruhe, Karlsruhe, Germany. 15. Department of Haematology and Oncology, University of Tübingen, Tübingen, Germany. 16. Department of Haematology, Medical Faculty, University of Duisburg-Essen, Essen, Germany. 17. Klinik für Innere Medizin I, Universität des Saarlandes, Homburg, Germany. 18. Department of Neurology, Ludwig-Maximilians-Universität, Munich, Germany. 19. Institute of Neuropathology, University Hospital of Cologne, Cologne, Germany. 20. Department of Neuroradiology, University Hospital Freiburg, Freiburg, Germany. 21. Department of Hematology, Oncology, and Stem-Cell Transplantation, University Medical Hospital and Faculty of Medicine, Albert-Ludwigs University, Freiburg, Germany. 22. Department of Haematology/Oncology and Palliative Care, Klinikum Stuttgart, Stuttgart, Germany.
Abstract
BACKGROUND: High-dose methotrexate-based chemotherapy is standard for primary CNS lymphoma, but most patients relapse. High-dose chemotherapy with autologous stem cell transplantation (HCT-ASCT) is supposed to overcome the blood-brain barrier and eliminate residual disease in the CNS. We aimed to investigate the safety and efficacy of HCT-ASCT in patients with newly diagnosed primary CNS lymphoma. METHODS: In this prospective, single-arm, phase 2 trial, we recruited patients aged 18-65 years with newly diagnosed primary CNS lymphoma and immunocompetence, with no limitation on clinical performance status, from 15 hospitals in Germany. Patients received five courses of intravenous rituximab 375 mg/m(2) (7 days before first high-dose methotrexate course and then every 10 days) and four courses of intravenous high-dose methotrexate 8000 mg/m(2) (every 10 days) and then two courses of intravenous rituximab 375 mg/m(2) (day 1), cytarabine 3 g/m(2) (days 2 and 3), and thiotepa 40 mg/m(2) (day 3). 3 weeks after the last course, patients commenced intravenous HCT-ASCT (rituximab 375 mg/m(2) [day 1], carmustine 400 mg/m(2) [day 2], thiotepa 2 × 5 mg/kg [days 3 and 4], and infusion of stem cells [day 7]), irrespective of response status after induction. We restricted radiotherapy to patients without complete response after HCT-ASCT. The primary endpoint was complete response at day 30 after HCT-ASCT in all registered eligible patients who received at least 1 day of study treatment. This trial is registered at ClinicalTrials.gov, number NCT00647049. FINDINGS: Between Jan 18, 2007, and May 23, 2011, we recruited 81 patients, of whom two (2%) were excluded, therefore we included 79 (98%) patients in the analysis. All patients started induction treatment; 73 (92%) commenced HCT-ASCT. 61 (77·2% [95% CI 66·1-86·6]) patients achieved a complete response. During induction treatment, the most common grade 3 toxicity was anaemia (37 [47%]) and the most common grade 4 toxicity was thrombocytopenia (50 [63%]). During HCT-ASCT, the most common grade 3 toxicity was fever (50 [68%] of 73) and the most common grade 4 toxicity was leucopenia (68 [93%] of 73). We recorded four (5%) treatment-related deaths (three [4%] during induction and one [1%] 4 weeks after HCT-ASCT). INTERPRETATION: HCT-ASCT with thiotepa and carmustine is an effective treatment option in young patients with newly diagnosed primary CNS lymphoma, but further comparative studies are needed. FUNDING: University Hospital Freiburg and Amgen.
BACKGROUND: High-dose methotrexate-based chemotherapy is standard for primary CNS lymphoma, but most patients relapse. High-dose chemotherapy with autologous stem cell transplantation (HCT-ASCT) is supposed to overcome the blood-brain barrier and eliminate residual disease in the CNS. We aimed to investigate the safety and efficacy of HCT-ASCT in patients with newly diagnosed primary CNS lymphoma. METHODS: In this prospective, single-arm, phase 2 trial, we recruited patients aged 18-65 years with newly diagnosed primary CNS lymphoma and immunocompetence, with no limitation on clinical performance status, from 15 hospitals in Germany. Patients received five courses of intravenous rituximab 375 mg/m(2) (7 days before first high-dose methotrexate course and then every 10 days) and four courses of intravenous high-dose methotrexate 8000 mg/m(2) (every 10 days) and then two courses of intravenous rituximab 375 mg/m(2) (day 1), cytarabine 3 g/m(2) (days 2 and 3), and thiotepa 40 mg/m(2) (day 3). 3 weeks after the last course, patients commenced intravenous HCT-ASCT (rituximab 375 mg/m(2) [day 1], carmustine 400 mg/m(2) [day 2], thiotepa 2 × 5 mg/kg [days 3 and 4], and infusion of stem cells [day 7]), irrespective of response status after induction. We restricted radiotherapy to patients without complete response after HCT-ASCT. The primary endpoint was complete response at day 30 after HCT-ASCT in all registered eligible patients who received at least 1 day of study treatment. This trial is registered at ClinicalTrials.gov, number NCT00647049. FINDINGS: Between Jan 18, 2007, and May 23, 2011, we recruited 81 patients, of whom two (2%) were excluded, therefore we included 79 (98%) patients in the analysis. All patients started induction treatment; 73 (92%) commenced HCT-ASCT. 61 (77·2% [95% CI 66·1-86·6]) patients achieved a complete response. During induction treatment, the most common grade 3 toxicity was anaemia (37 [47%]) and the most common grade 4 toxicity was thrombocytopenia (50 [63%]). During HCT-ASCT, the most common grade 3 toxicity was fever (50 [68%] of 73) and the most common grade 4 toxicity was leucopenia (68 [93%] of 73). We recorded four (5%) treatment-related deaths (three [4%] during induction and one [1%] 4 weeks after HCT-ASCT). INTERPRETATION: HCT-ASCT with thiotepa and carmustine is an effective treatment option in young patients with newly diagnosed primary CNS lymphoma, but further comparative studies are needed. FUNDING: University Hospital Freiburg and Amgen.
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