Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone combined with high-dose methotrexate plus intrathecal chemotherapy for newly diagnosed intravascular large B-cell lymphoma (PRIMEUR-IVL): long-term results of a multicentre, single-arm, phase 2 trial.

in EClinicalMedicine by Kazuyuki Shimada, Motoko Yamaguchi, Yachiyo Kuwatsuka, Kosei Matsue, Keijiro Sato, Shigeru Kusumoto, Hirokazu Nagai, Jun Takizawa, Noriko Fukuhara, Koji Nagafuji, Kana Miyazaki, Eiichi Ohtsuka, Akinao Okamoto, Yasumasa Sugita, Toshiki Uchida, Satoshi Kayukawa, Atsushi Wake, Daisuke Ennishi, Yukio Kondo, Akiko Meguro, Yoshihiro Kin, Yosuke Minami, Daigo Hashimoto, Takahiro Nishiyama, Satoko Shimada, Yasufumi Masaki, Masataka Okamoto, Yoshiko Atsuta, Hitoshi Kiyoi, Ritsuro Suzuki, Shigeo Nakamura, Tomohiro Kinoshita

TLDR

  • The PRIMEUR-IVL study showed that standard chemotherapy combined with CNS-directed therapy for untreated IVLBCL patients resulted in a 2-year PFS rate of 76% and 2-year OS rate of 92%, with a low incidence of secondary CNS involvement (3%).
  • The study suggests that this treatment regimen may be an effective option for IVLBCL patients, with durable responses and low toxicity observed at 5-year follow-up.

Abstract

Intravascular large B-cell lymphoma (IVLBCL) is a rare type of extranodal large B-cell lymphoma for which prognosis is typically poor without a timely diagnosis. To explore the safety and efficacy of standard chemotherapy combined with central nervous system (CNS)-directed therapy, we conducted a multicentre, single-arm, phase 2 trial in untreated IVLBCL patients without CNS involvement at diagnosis (PRIMEUR-IVL). In the primary analysis, the PRIMEUR-IVL study demonstrated 2-year progression-free survival (PFS) of 76% and 2-year overall survival (OS) of 92% with a low incidence (3%) of secondary CNS involvement (sCNSi). We present a prespecified final analysis of the PRIMEUR-IVL study including 5-year PFS, OS and cumulative incidence of sCNSi. Participants were enrolled between June 2011 and July 2016, and the data cutoff date for the final analysis was 16 November 2021. The trial was registered in the UMIN Clinical Trial Registry (UMIN000005707) and the Japan Registry of Clinical Trials (jRCTs041180165). With a median follow-up of 7.1 years (interquartile range 5.6-8.7), 5-year PFS in all 37 eligible patients was 68% (95% confidence interval [CI] 50%-80%) and OS was 78% (95% CI 61%-89%). No additional sCNSi was observed after the primary analysis. Severe adverse events after the primary analysis were grade 4 neutropenia (n = 1) and grade 4 myelodysplastic syndrome that did not require specific treatment (n = 1). Eight deaths occurred during the observation period after enrolment, due to primary disease (n = 6), sepsis (n = 1) and unknown sudden death (n = 1). Long-term follow-up data demonstrated durable response for PFS and OS, and low cumulative incidence of sCNSi, indicating the efficacy of standard chemotherapy combined with CNS-directed therapy for untreated IVLBCL patients. This study received financial support from the Japan Agency for Medical Research and Development, Center for Supporting Hematology-Oncology Studies, and National Cancer Center.

Overview

  • The study aimed to investigate the safety and efficacy of standard chemotherapy combined with central nervous system (CNS)-directed therapy for untreated intravascular large B-cell lymphoma (IVLBCL) patients without CNS involvement at diagnosis.
  • The multicenter, single-arm, phase 2 trial enrolled 37 patients between June 2011 and July 2016, and the study had a median follow-up of 7.1 years.
  • The primary objective of the study was to assess the 2-year progression-free survival (PFS) and overall survival (OS) rates for IVLBCL patients.

Comparative Analysis & Findings

  • The 2-year PFS rate was 76%, and the 2-year OS rate was 92% with a low incidence of secondary CNS involvement (3%); these results showed the efficacy of standard chemotherapy combined with CNS-directed therapy.
  • The final analysis showed 5-year PFS and OS rates of 68% and 78%, respectively, and cumulative incidence of secondary CNS involvement (sCNSi) remained low, indicating durable responses and low toxicity.
  • No additional sCNSi was observed after the primary analysis, and severe adverse events were limited to one case each of grade 4 neutropenia and grade 4 myelodysplastic syndrome, both of which were managed with standard treatment.

Implications and Future Directions

  • The study suggests that standard chemotherapy combined with CNS-directed therapy may be an effective treatment regimen for IVLBCL patients, which may improve patient outcomes and quality of life.
  • Future studies should focus on identifying predictive biomarkers to stratify patients for CNS-directed therapy, and on developing targeted therapies for IVLBCL.
  • The study highlights the importance of long-term follow-up in studying cancer patients, as it provides valuable insights into durability of responses and cumulative incidence of secondary events.
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