Kazuyuki Shimada1, Motoko Yamaguchi2, Yoshiko Atsuta3, Kosei Matsue4, Keijiro Sato5, Shigeru Kusumoto6, Hirokazu Nagai7, Jun Takizawa8, Noriko Fukuhara9, Koji Nagafuji10, Kana Miyazaki2, Eiichi Ohtsuka11, Masataka Okamoto12, Yasumasa Sugita13, Toshiki Uchida14, Satoshi Kayukawa15, Atsushi Wake16, Daisuke Ennishi17, Yukio Kondo18, Tohru Izumi19, Yoshihiro Kin20, Kunihiro Tsukasaki21, Daigo Hashimoto22, Masaaki Yuge23, Atsumi Yanagisawa3, Yachiyo Kuwatsuka24, Satoko Shimada25, Yasufumi Masaki26, Nozomi Niitsu27, Hitoshi Kiyoi28, Ritsuro Suzuki29, Takashi Tokunaga7, Shigeo Nakamura25, Tomohiro Kinoshita30. 1. Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan. Electronic address: kshimada@med.nagoya-u.ac.jp. 2. Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu, Japan. 3. Japanese Data Center for Hematopoietic Cell Transplantation, Nagoya, Japan. 4. Division of Hematology/Oncology, Internal Medicine, Kameda Medical Center, Kamogawa, Japan. 5. Department of Hematology, Nagano Red Cross Hospital, Nagano, Japan. 6. Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan. 7. Department of Hematology, National Hospital Organization Nagoya Medical Center, Nagoya, Japan. 8. Department of Hematology, Endocrinology and Metabolism, Niigata University Faculty of Medicine, Niigata, Japan. 9. Department of Hematology and Rheumatology, Tohoku University Hospital, Sendai, Japan. 10. Division of Hematology and Oncology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan. 11. Department of Hematology, Oita Prefectural Hospital, Oita, Japan. 12. Department of Hematology, Fujita Health University School of Medicine, Toyoake, Aichi, Japan. 13. Department of Hematology, Oami Municipal Hospital, Oamishirasato, Japan. 14. Department of Hematology and Oncology, Japanese Red Cross Nagoya Daini Hospital, Nagoya, Japan. 15. Department of Clinical Oncology, Nagoya Memorial Hospital, Nagoya, Japan. 16. Department of Hematology, Toranomon Hospital Kajigaya, Kawasaki, Japan. 17. Department of Hematology and Oncology, Okayama University Hospital, Okayama, Japan. 18. Department of Internal Medicine, Toyama Prefectural Central Hospital, Toyama, Japan. 19. Division of Hematology, Tochigi Cancer Center, Utsunomiya, Japan. 20. Department of Hematology, Daini Osaka Police Hospital, Osaka, Japan. 21. Department of Hematology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan. 22. Department of Hematology, Hokkaido University Faculty of Medicine, Graduate School of Medicine, Sapporo, Japan. 23. Division of Hematology, Ichinomiya Municipal Hospital, Ichinomiya, Japan. 24. Japanese Data Center for Hematopoietic Cell Transplantation, Nagoya, Japan; Department of Advanced Medicine, Nagoya University Hospital, Nagoya, Japan. 25. Department of Pathology and Clinical Laboratories, Nagoya University Hospital, Nagoya, Japan. 26. Department of Hematology and Immunology, Kanazawa Medical University, Uchinada, Japan. 27. International Medical Center, Saitama Medical University, Hidaka, Japan. 28. Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan. 29. Department of HSCT Data Management and Biostatistics, Nagoya University School of Medicine, Nagoya, Japan. 30. Division of Hematology and Cell Therapy, Aichi Cancer Center, Nagoya, Japan.
Abstract
BACKGROUND: Intravascular large B-cell lymphoma (IVLBCL) is a rare disease for which there is no available standard treatment. We aimed to ascertain the safety and activity of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) with high-dose methotrexate and intrathecal chemotherapy as CNS-oriented therapy for patients with previously untreated IVLBCL. METHODS: PRIMEUR-IVL is a multicentre, single-arm, phase 2 trial at 22 hospitals in Japan. Eligible patients had untreated histologically confirmed IVLBCL, were aged 20-79 years, had an Eastern Cooperative Group performance status of 0-3, and had no apparent CNS involvement at diagnosis. Patients received three cycles of R-CHOP (rituximab 375 mg/m2 intravenously on day 1 [except cycle one, which was on day 8]; cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1·4 mg/m2 [maximum 2·0 mg] intravenously on day 1 of cycle one and day 2 of cycles two and three; and prednisolone 100 mg/day orally on days 1-5 of cycle one and days 2-6 of cycles two and three) followed by two cycles of rituximab with high-dose methotrexate (3·5 g/m2 intravenously on day 2 of cycles four and five) every 2 weeks and three additional cycles of R-CHOP. Intrathecal chemotherapy (methotrexate 15 mg, cytarabine 40 mg, and prednisolone 10 mg) was administered four times during the R-CHOP phase. The primary endpoint was 2-year progression-free survival. Efficacy analyses were done in all enrolled patients; safety analyses were done in all enrolled and treated patients. The trial is registered in the UMIN Clinical Trials Registry (UMIN000005707) and the Japan Registry of Clinical Trials (jRCTs041180165); the trial is ongoing for long-term follow-up. FINDINGS: Between June 16, 2011, and July 21, 2016, 38 patients were enrolled, of whom 37 were eligible; one patient was excluded because of a history of testicular lymphoma. Median follow-up was 3·9 years (IQR 2·5-5·5). 2-year progression-free survival was 76% (95% CI 58-87). The most frequent adverse events of grade 3-4 were neutropenia and leucocytopenia, which were reported in all 38 (100%) patients. Serious adverse events were hypokalaemia, febrile neutropenia with hypotension, hypertension, and intracerebral haemorrhage (reported in one [3%] patient each). No treatment-related deaths occurred during protocol treatment. INTERPRETATION: R-CHOP combined with rituximab and high-dose methotrexate plus intrathecal chemotherapy is a safe and active treatment for patients with IVLBCL without apparent CNS involvement at diagnosis, and this regimen warrants future investigation. FUNDING: The Japan Agency for Medical Research and Development, the Center for Supporting Hematology-Oncology Trials, and the National Cancer Center.
BACKGROUND: Intravascular large B-cell lymphoma (IVLBCL) is a rare disease for which there is no available standard treatment. We aimed to ascertain the safety and activity of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) with high-dose methotrexate and intrathecal chemotherapy as CNS-oriented therapy for patients with previously untreated IVLBCL. METHODS: PRIMEUR-IVL is a multicentre, single-arm, phase 2 trial at 22 hospitals in Japan. Eligible patients had untreated histologically confirmed IVLBCL, were aged 20-79 years, had an Eastern Cooperative Group performance status of 0-3, and had no apparent CNS involvement at diagnosis. Patients received three cycles of R-CHOP (rituximab 375 mg/m2 intravenously on day 1 [except cycle one, which was on day 8]; cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1·4 mg/m2 [maximum 2·0 mg] intravenously on day 1 of cycle one and day 2 of cycles two and three; and prednisolone 100 mg/day orally on days 1-5 of cycle one and days 2-6 of cycles two and three) followed by two cycles of rituximab with high-dose methotrexate (3·5 g/m2 intravenously on day 2 of cycles four and five) every 2 weeks and three additional cycles of R-CHOP. Intrathecal chemotherapy (methotrexate 15 mg, cytarabine 40 mg, and prednisolone 10 mg) was administered four times during the R-CHOP phase. The primary endpoint was 2-year progression-free survival. Efficacy analyses were done in all enrolled patients; safety analyses were done in all enrolled and treated patients. The trial is registered in the UMIN Clinical Trials Registry (UMIN000005707) and the Japan Registry of Clinical Trials (jRCTs041180165); the trial is ongoing for long-term follow-up. FINDINGS: Between June 16, 2011, and July 21, 2016, 38 patients were enrolled, of whom 37 were eligible; one patient was excluded because of a history of testicular lymphoma. Median follow-up was 3·9 years (IQR 2·5-5·5). 2-year progression-free survival was 76% (95% CI 58-87). The most frequent adverse events of grade 3-4 were neutropenia and leucocytopenia, which were reported in all 38 (100%) patients. Serious adverse events were hypokalaemia, febrile neutropenia with hypotension, hypertension, and intracerebral haemorrhage (reported in one [3%] patient each). No treatment-related deaths occurred during protocol treatment. INTERPRETATION: R-CHOP combined with rituximab and high-dose methotrexate plus intrathecal chemotherapy is a safe and active treatment for patients with IVLBCL without apparent CNS involvement at diagnosis, and this regimen warrants future investigation. FUNDING: The Japan Agency for Medical Research and Development, the Center for Supporting Hematology-Oncology Trials, and the National Cancer Center.
Authors: Thomas Breakell; Heidi Waibel; Stefan Schliep; Barbara Ferstl; Michael Erdmann; Carola Berking; Markus V Heppt Journal: Curr Oncol Date: 2022-04-19 Impact factor: 3.109