Immuno-chemotherapy with a combination of rituximab, methotrexate, pirarubicin and procarbazine for patients with primary CNS lymphoma—A preliminary report

Yamanaka, Ryuya; Homma, Junpei; Sano, Masakazu; Tsuchiya, Naoto; Yajima, Naoki; Shinbo, Yoshikatsu; Hasegawa, Akira; Onda, Kiyoshi; Tanaka, Ryuichi

doi:10.1080/10428190701248009

Cited by 10 publications

(5 citation statements)

References 13 publications

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“…Primary CNS lymphoma (PCNSL) is a rare and highly aggressive lymphoma that arises in the intracerebral or intraocular spaces without systemic involvement. In agreement with previous studies (31), we found that PCNSL had a worse prognosis than systemic DLBCL in any setting analyzed.…”

Section: Discussionsupporting

confidence: 93%

Clinical features and outcomes of diffuse large B-cell lymphoma based on nodal or extranodal primary sites of origin: Analysis of 1,085 WHO classified cases in a single institution in China

Shi¹,

Han²,

Yang³

et al. 2019

Chinese Journal of Cancer Research

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ObjectiveTo explore the clinicobiologic features and outcomes of diffuse large B-cell lymphoma (DLBCL) patients in China according to the primary site.MethodsA total of 1,085 patients diagnosed with DLBCL in National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College during a 6-year period were enrolled. Their clinical characteristics and outcomes were analyzed according to the primary site.ResultsIn the 1,085 patients, 679 (62.6%) cases were nodal DLBCL (N-DLBCL) and 406 cases (37.4%) were extranodal DLBCL (EN-DLBCL). The most common sites of N-DLBCL were lymphonodus (64.8%), Waldeyer’s ring (19.7%), mediastinum (12.8%) and spleen (2.7%), while in EN-DLBCL, stomach (22.4%), intestine (16.0%), nose and sinuses (8.9%), testis (8.4%), skin (7.9%), thyroid (6.9%), central nervous system (CNS) (6.4%), breast (5.7%), bone (3.4%), and salivary gland (2.7%) were most common. N-DLBCL patients tend to present B symptoms, bulky disease, and elevated LDH more often, while age >60 years, extranodal sites >1, Ann Arbor stage I or II, bone marrow involvement, and Ki-67 index >90% were usually seen in EN-DLBCL. The 5-year overall survival (OS) rate and progression-free survival (PFS) rate for all patients were 62.5% and 54.2%. The 5-year OS rate for patients with N-DLBCL and EN-DLBCL were 65.5% and 56.9% (P=0.008), and the 5-year PFS were 57.0% and 49.0% (P=0.020). Waldeyer’s ring originated DLBCL possessed the highest 5-year OS rate (83.6%) and PFS rate (76.9%) in N-DLBCL. The top five EN-DLBCL subtypes with favorable prognosis were stomach, breast, nose and sinuses, lung, salivary gland, with 5-year OS rate: 70.3%, 69.6%, 69.4%, 66.7% and 63.6%, respectively. While CNS, testis, oral cavity and kidney originated EN-DLBCL faced miserable prognosis, with 5-year OS rate of 26.9%, 38.2%, and 42.9%.ConclusionsIn our study, primary sites were associated with clinical characteristics and outcomes. Compared with EN-DLBCL, N-DLBCL had better prognosis.

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Section: Discussionsupporting

confidence: 93%

Clinical features and outcomes of diffuse large B-cell lymphoma based on nodal or extranodal primary sites of origin: Analysis of 1,085 WHO classified cases in a single institution in China

Shi¹,

Han²,

Yang³

et al. 2019

Chinese Journal of Cancer Research

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“…www.nature.com/scientificreports www.nature.com/scientificreports/ MTX-based chemoradiotherapy is a standard first-line treatment for PCNSL, results in a median OS of 25-51 months 29 . However, most PCNSL patients fail the treatment 29,30 . Thus, salvage therapies should be optimized by the chemotherapy regimen for second-line treatments 29,30 .…”

Section: Discussionmentioning

confidence: 99%

“…However, most PCNSL patients fail the treatment 29,30 . Thus, salvage therapies should be optimized by the chemotherapy regimen for second-line treatments 29,30 . A recent study has demonstrated that IC 50 for MTX in HKBML-MTX is markedly higher than TK-MTX and Raji-MTX 13 .…”

Section: Discussionmentioning

confidence: 99%

GSEA-assisted gene signatures valid for combinations of prognostic markers in PCNSL

Takashima¹,

Hamano

Fukai

et al. 2020

Sci Rep

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Primary central nervous system lymphoma (PCNSL) is a brain malignant non-Hodgkin's B-cell lymphoma. The standard treatments are high-dose methotrexate (MTX)-based chemotherapies and deferred whole brain radiotherapy. However, MTX resistance-dependent global expression and signaling pathway changes and their relationship with prognoses have not yet been elucidated. Here, we conducted a global expression analysis with next-generation sequencing and gene set enrichment analysis (GSEA) in MTX-resistant PCNSL cell lines (HKBML-MTX and TK-MTX) and PCNSL tissues. In rank scores, genes listed in HKBML-MTX and TK-MTX were enriched in PCNSL with poor prognoses. In fold changes, a part of differentially-expressed genes in PCNSL tissues were also detected in HKBML-MTX and TK-MTX cells; FOXD2-AS1 and MMP19 were commonly expressed in both HKBML-MTX and TK-MTX, FABP5 and CD70 were HKBML-MTX-specifically expressed, and CLCN2, HOXB9, INE1, and LRP5L were TK-MTX-specifically expressed, which may provide a combination of prognostic markers on MTX-sensitivities in PCNSL. Additionally, PCNSL subgroups, divided with hierarchical clustering and Kaplan-Meier methods, included twenty commonly expressed genes in both HKBML-MTX and TK-MTX, ten HKBML-MTX-specifically expressed genes, and two TK-MTX-specifically expressed genes. these results suggest that the GSeA-assisted gene signatures can provide a combination for prognostic markers in recurrent PCNSL with MTX resistances. Primary central nervous system lymphoma (PCNSL) is a rare subtype of cerebral malignant non-Hodgkin's B-cell lymphoma with a median overall survival (OS) of approximately four years, which accounts for 3% of all primary brain tumors and 1% of non-Hodgkin's lymphomas (NHLs) in adults 1,2. Methotrexate (MTX) is an antifolate that inhibits dihydrofolate (DHF) reductase (DHFR) activity in purine and thymidine syntheses and regulates the expression of glucocorticoid receptors α and β in human blood cells in vitro 3,4. High-dose MTX (HD-MTX) is used as a first-line treatment in PCNSL 5. Second-line treatments are also required for 10-35% of patients with refractory diseases and for another 35-60% or more who have relapse-acquired MTX resistances 6. Thus, almost PCNSLs recur with MTX resistances despite standard treatments 7. MTX is an antifolate that inhibits DNA synthesis 4. DHFR converts DHF to tetrahydrofolate (THF), a basic form of reduced folate coenzymes 8. MTX resistances are acquired through alternative intrinsic mechanisms in malignant cells, which include decreased drug transport due to mutations and reduced transcription activity of folate carrier genes, dysregulated DHFR activity and affinity, and decreased polyglutamination of MTX due to decreased folylpolyglutamate synthetase (FPGS) activity and increased γ-glutamyl hydrolase (GGH) activity 9-11. MTX exposure induces the activity of methylenetetrahydrofolate dehydrogenase 1 (MTHFD1), serine hydroxymethyltransferase 1 (SHMT1), 5,10-methylenetetrahydrofolate reductase (MTHFR), 5-methyltetrahydrofolate-homocystein...

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“…Promising preliminary data suggest efficacy of adding to MTX the drugs Temodar [33] and Rituxan [38]; the provision of autologous stem cell transplantation [39, 40] and low dose brain radiation. These trials are ongoing.…”

Section: Discussionmentioning

confidence: 99%

Monotherapy with methotrexate for primary central nervous lymphoma has single agent activity in the absence of radiotherapy: a single institution cohort

et al. 2009

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We have retrospectively reviewed toxicities and response of a cohort of primary central nervous system lymphoma (PCNSL) patients treated with high dose parenteral methotrexate (MTX) monotherapy without whole brain radiation. From The Massachusetts General Hospital (MGH) Cancer Registry, active since 1946, we selected all immunocompetent patients with histologic and/or radiographic PCNSL diagnosed between 1980 and 2007. We identified the recipients of MTX with leucovorin rescue as sole therapy. No patient received radiation therapy (XRT). We analyzed this cohort for toxicity, response and patterns of recurrence. The cohort of 121 patients received on average 11 cycles of intravenous MTX at a median dose of 8 g/m2. Median interval between cycles was 10 days. After 3 months of therapy, the overall response rate was 85% (58% CR, 27% PR). The overall survival (OS) for the cohort was 7 years and progression-free survival (PFS) was 3.14 years. A trend toward a higher PFS was seen in patients who continued to receive MTX (3.48 years) every three months as compared to patients who ceased MTX after one year (2.86 years). Of 68 patients who achieved initial CR, there were 40 recurrences. Twenty-six of the 40 were re-induced with MTX as above; Sixty-nine percent again achieved CR. Eighty-one treatment-related toxicities occurred in 1316 MTX cycles. These toxicities included MRI white matter changes (N = 8) and lead to MTX cessation in 16 patients. High-dose MTX monotherapy of PCNSL is well-tolerated and provides PFS of >3 years and OS >7 years.

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Immuno-chemotherapy with a combination of rituximab, methotrexate, pirarubicin and procarbazine for patients with primary CNS lymphoma—A preliminary report

Cited by 10 publications

References 13 publications

Clinical features and outcomes of diffuse large B-cell lymphoma based on nodal or extranodal primary sites of origin: Analysis of 1,085 WHO classified cases in a single institution in China

Clinical features and outcomes of diffuse large B-cell lymphoma based on nodal or extranodal primary sites of origin: Analysis of 1,085 WHO classified cases in a single institution in China

GSEA-assisted gene signatures valid for combinations of prognostic markers in PCNSL

Monotherapy with methotrexate for primary central nervous lymphoma has single agent activity in the absence of radiotherapy: a single institution cohort

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