Publications by authors named "Motoko Yamaguchi"

86 Publications

A phase 2 study of polatuzumab vedotin + bendamustine + rituximab in relapsed/refractory diffuse large B-cell lymphoma.

Cancer Sci 2021 Jul 4;112(7):2845-2854. Epub 2021 Jun 4.

Department of Hematology and Oncology, Osaka University Hospital, Osaka, Japan.

Polatuzumab vedotin (pola) is a CD79b-targeted antibody-drug conjugate delivering a potent antimitotic agent (monomethyl auristatin E) to B cells. This was an open-label, single-arm study of pola 1.8 mg/kg, bendamustine 90 mg/m , rituximab 375 mg/m (pola + BR) Q3W for up to six cycles in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL) who received ≥1 prior line of therapy and were ineligible for autologous stem cell transplantation (ASCT) or experienced treatment failure with prior ASCT. Primary endpoint was complete response rate (CRR) at the end of the treatment (EOT) by positron emission tomography-computed tomography (PET-CT) using modified Lugano Response Criteria. Secondary endpoints included efficacy, safety, and pharmacokinetics. Thirty-five patients (median age 71 [range 46-86] years) were enrolled. Twenty-three (66%) patients had refractory disease, and 23 (66%) had ≥2 prior lines of therapy. At a median follow-up of 5.4 (0.7-11.9) months, patients received a median of five treatment cycles. CRR was 34.3% (95% confidence interval [CI] 19.1-52.2) at EOT. Overall response rate was 42.9% at EOT, and median progression-free survival was 5.2 months (95% CI 3.6-not evaluable). Median overall survival was not reached. No fatal adverse events (AEs) were observed. Grade 3-4 AEs were mainly hematological: anemia (37%), neutropenia (31%), white blood cell count decreased (23%), thrombocytopenia/platelet count decreased/neutrophil count decreased (20% each), and febrile neutropenia (11%). Grade 1-2 peripheral neuropathy (PN; sensory and/or motor) was reported in 14% of patients; there were no ≥grade 3 PN events. This study (JapicCTI-184048) demonstrated the efficacy and safety of pola + BR in Japanese patients with R/R DLBCL who were ineligible for ASCT.
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http://dx.doi.org/10.1111/cas.14937DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8253277PMC
July 2021

Clinical characteristics of patients with B-cell lymphoma enrolled in clinical trials for aggressive lymphoma in Japan: Japan Clinical Oncology Group - Lymphoma Study Group study - JCOG0108A.

J Clin Exp Hematop 2021 ;61(1):35-41

National Cancer Center Hospital, Tokyo, Japan.

The clinical characteristics of B-cell lymphoma (BCL) were studied through the combined analysis of six clinical trials conducted by the Japan Clinical Oncology Group - Lymphoma Study Group (JCOG-LSG) for aggressive lymphoma in the 1990s, before the introduction of rituximab. Through a central pathological review, 829 patients were diagnosed with BCL according to the World Health Organization classification and treated with doxorubicin-containing combination chemotherapies. Of these patients, 642, 104, 30, and 24 patients were diagnosed with diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL), respectively. The overall survival (OS) of FL and MZL patients was higher than that of patients with DLBCL and MCL. The OS of the MCL patients was higher than that of DLBCL patients in the first 5 years, but MCL had the lowest survival after 5 years. The OS of DLBCL patients was clearly stratified by the international prognostic index and showed data compatible with that of aggressive lymphoma in the pre-rituximab era. These results established the clinical aspects of BCL in a large number of patients treated in prospective studies during the pre-rituximab era in Japan.
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http://dx.doi.org/10.3960/jslrt.20062DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8053572PMC
May 2021

Early central nervous system relapse of monomorphic epitheliotropic intestinal T-cell lymphoma after cord blood transplantation.

Int J Hematol 2021 Jul 1;114(1):129-135. Epub 2021 Mar 1.

Department of Hematology and Oncology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan.

Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL) is a rare subtype of intestinal T-cell lymphoma that occurs mostly in Asia. CHOP-like therapy is usually selected, but the prognosis is very poor. This report concerns a 43-year-old woman with newly diagnosed stage IVA MEITL. The patient obtained a partial response after 4 cycles of GDP (gemcitabine, dexamethasone, cisplatin) and achieved a complete response (CR) after cord blood transplantation (CBT) conditioned with total body irradiation, cyclophosphamide, and cytarabine. Seven months after transplantation, the patient experienced cognitive impairment. Magnetic resonance imaging of the brain showed a high-intensity lesion in the right cerebral peduncle and internal capsule. A cerebrospinal fluid examination confirmed central nervous system (CNS) relapse of MEITL. After 3 cycles of MPV (methotrexate, procarbazine, vincristine) followed by whole-brain radiotherapy, her cognitive impairment improved. Due to disease progression, she died 6 months after CNS relapse. Given the CNS relapse after achieving a CR with GDP and CBT in this patient, CNS prophylaxis during first-line therapy may be beneficial in the treatment of MEITL.
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http://dx.doi.org/10.1007/s12185-021-03107-9DOI Listing
July 2021

DA-EPOCH-R combined with high-dose methotrexate in patients with newly diagnosed stage II-IV CD5-positive diffuse large B-cell lymphoma: a single-arm, open-label, phase II study.

Haematologica 2020 09 1;105(9):2308-2315. Epub 2020 Sep 1.

Department of Hematology and Oncology, Mie University Graduate School of Medicine, Mie.

CD5-positive diffuse large B-cell lymphoma (CD5+ DLBCL) is characterized by poor prognosis and a high frequency of central nervous system relapse after standard immunochemotherapy. We conducted a phase II study to investigate the efficacy and safety of dose-adjusted (DA)- EPOCH-R (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) combined with high-dose methotrexate (HD-MTX) in newly diagnosed patients with CD5+ DLBCL. Previously untreated patients with stage II to IV CD5+ DLBCL according to the 2008 World Health Organization classification were eligible. Four cycles of DA-EPOCH-R followed by two cycles of HD-MTX and four additional cycles of DAEPOCH- R (DA-EPOCH-R/HD-MTX) were planned as the protocol treatment. The primary end point was 2-year progression-free survival (PFS). Between September 25, 2012, and November 11, 2015, we enrolled 47 evaluable patients. Forty-five (96%) patients completed the protocol treatment. There were no deviations or violations in the DA-EPOCH-R dose levels. The complete response rate was 91%, and the overall response rate was 94%. At a median follow up of 3.1 years (range, 2.0-4.9 years), the 2- year PFS was 79% [95% confidence interval (CI): 64-88]. The 2-year overall survival was 89% (95%CI: 76-95). Toxicity included grade 4 neutropenia in 46 (98%) patients, grade 4 thrombocytopenia 12 (26%) patients, and febrile neutropenia in 31 (66%) patients. No treatment-related death was noted during the study. DA-EPOCH-R/HD-MTX might be a first-line therapy option for stage II-IV CD5+ DLBCL and warrants further investigation. (Trial registered at: UMIN-CTR: UMIN000008507.).
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http://dx.doi.org/10.3324/haematol.2019.231076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556618PMC
September 2020

Dose-adjusted EPOCH with or without rituximab for aggressive lymphoma patients: real world data.

Int J Hematol 2020 Dec 3;112(6):807-816. Epub 2020 Sep 3.

Innovative Cancer Center/Oncology-Hematology, Shimane University Hospital, 89-1 Enya, Izumo, Shimane, 693-8501, Japan.

CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone) -/+ rituximab (R) is the standard chemotherapeutic regimen for aggressive lymphoma, but is insufficient for aggressive lymphoma with adverse prognostic factors. Dose-adjusted (DA)-EPOCH (etoposide, doxorubicin, cyclophosphamide, vincristine, and prednisolone) -/+ R demonstrates excellent efficacy against some aggressive lymphoma. Thus, we conducted a retrospective study to evaluate the feasibility and efficacy of this therapy in clinical practice. We enrolled 149 patients from 17 institutions diagnosed between 2007 and 2015. The median follow-up period for survivors was 27 months (range 0.2-123). The complete response (CR) rate of newly diagnosed patients was 79% (95% CI 68-87%). All patients were hospitalized to receive this therapy and 94% of patients also received granulocyte-colony-stimulating factor support. There were no treatment-related deaths. Febrile neutropenia (FN) and grade 3 or 4 infection occurred in 55% and 28% of patients, respectively. There were no significant differences in FN or infection between young (≤ 65 years) and elderly patients (> 65 years). In newly diagnosed diffuse large B-cell lymphoma-not otherwise specified patients (n = 46), the CR rate was 80% (95% CI 64-91%) and the 2-year OS rate was 81% (95% CI 66-90%). In the present study, DA-EPOCH -/+ R exhibited excellent efficacy and feasibility for aggressive lymphoma.
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http://dx.doi.org/10.1007/s12185-020-02984-wDOI Listing
December 2020

Prediction and prevention of central nervous system relapse in patients with extranodal natural killer/T-cell lymphoma.

Blood 2020 11;136(22):2548-2556

Division of Hematology-Oncology, Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, South Korea.

Because non-anthracycline-based chemotherapy with l-asparaginase has improved survival outcomes in patients with extranodal natural killer/T-cell lymphoma (ENKTL), the incidence of central nerve system (CNS) relapse can be different when compared with that in previous reports. In this research, we sought to identify the incidence of and predictors for CNS relapse and to evaluate the necessity of CNS prophylaxis with intermediate-dose methotrexate (ID-MTX). The records of 399 patients in the training cohort and 253 patients in the validation cohort with ENKTL who received non-anthracycline-based chemotherapy were reviewed. Patients were divided into 2 groups according to whether the chemotherapy regimen included ID-MTX above 2 g/m2. A new central nervous system-prognostic index of natural killer (CNS-PINK) model was developed using 1-point powerful predictors of CNS relapse (PINK; hazard ratio [HR], 2.908; P = .030 and extranodal involvement [≥2]; HR, 4.161; P = .001) and was calculated as a sum of scores. The high-risk group of CNS-PINK was defined as 2 points. The cumulative incidence of CNS relapse was different between the CNS-PINK risk groups in the training (P < .001) and validation (P = .038) cohorts. Patients in the high-risk CNS-PINK group who were treated with SMILE or SMILE-like regimens with ID-MTX (S-ID-MTX) displayed a lower incidence rate of CNS relapse than did those who received other regimens without ID-MTX in the training cohort (P = .029). The CNS-PINK was demonstrated its strong predictability of CNS relapse in ENKTL patients. The effectiveness of S-ID-MTX in preventing CNS events in high-risk CNS-PINK patients should be verified in future studies.
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http://dx.doi.org/10.1182/blood.2020005026DOI Listing
November 2020

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

Lancet Oncol 2020 04 11;21(4):593-602. Epub 2020 Mar 11.

Department of Hematology and Oncology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

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/m intravenously on day 1 [except cycle one, which was on day 8]; cyclophosphamide 750 mg/m, doxorubicin 50 mg/m, and vincristine 1·4 mg/m [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/m 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.
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http://dx.doi.org/10.1016/S1470-2045(20)30059-0DOI Listing
April 2020

Genetic polymorphisms and vincristine-induced peripheral neuropathy in patients treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone therapy.

Int J Hematol 2020 May 28;111(5):686-691. Epub 2020 Jan 28.

Department of Hematology and Oncology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan.

Vincristine (VCR)-induced peripheral neuropathy (VIPN) is a common and life-long toxicity in lymphoma patients receiving current standard chemotherapy. The association between VIPN and genetic polymorphisms is largely unknown in adult lymphoma patients. To examine the possible relationship between known genetic polymorphisms in patients with pediatric acute lymphoblastic leukemia and incidence of VIPN in adult patients with B cell lymphoma, we examined CEP72 rs924607, ETAA1 rs17032980, MTNR1B rs12786200, CYP3A5 rs776746, rs7963521, and rs1045644 genetic polymorphisms in samples from 56 adult patients with B-cell lymphoma who received rituximab, cyclophosphamide, doxorubicin, VCR, and prednisone (R-CHOP) chemotherapy. Mutation analysis was performed by direct sequencing. The median age was 65 years (range 30-79). The median cumulative dose of VCR was 12 mg (range 2-16). VIPN was documented in 42 patients (75%), and 9 (16%) had grade 2-4 VIPN. Age, impaired glucose tolerance, number of cycles of R-CHOP, and VCR cumulative dose were not associated with incidence of VIPN. There was no association between the incidence of grade 2-4 or any grade VIPN and these six genetic polymorphisms. These results indicate that CEP72, MTNR1B, ETAA1, CYP3A5, rs7963521, and rs1045644 genetic polymorphisms are not associated with VIPN in patients with B-cell lymphoma who received R-CHOP.
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http://dx.doi.org/10.1007/s12185-020-02832-xDOI Listing
May 2020

Improved prognosis of extranodal NK/T cell lymphoma, nasal type of nasal origin but not extranasal origin.

Ann Hematol 2019 Jul 19;98(7):1647-1655. Epub 2019 Apr 19.

Department of Hematology and Oncology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan.

Extranodal NK/T cell lymphoma (NKTCL), nasal type (ENKL) that shows no apparent nasal involvement, is termed extranasal NKTCL or non-nasal NKTCL. In this study, we aimed to explore therapeutic approaches and outcomes in patients with extranasal NKTCL in current clinical practice. A data set of patients with newly diagnosed NKTCL who were diagnosed at 31 institutes in Japan between 2000 and 2013 was used for analysis. The patients' fitness for steroid, methotrexate, ifosfamide, L-asparaginase, and etoposide (SMILE) chemotherapy was assessed using the major inclusion criteria of the SMILE phase 2 study. Of 358 patients, 47 (13%) had extranasal NKTCL. The most frequent extranodal sites of involvement in extranasal NKTCL were skin/subcutaneous tissue (n = 18). Six (13%) of the patients with extranasal NKTCL had localized disease and were diagnosed before 2010. With a median follow-up of 5.8 years, the 2-year overall survival (OS) in patients with nasal and extranasal NKTCL was 70% (95% confidence interval [CI], 65-75%) and 34% (95% CI, 21-47%), respectively. OS in patients with nasal NKTCL had a trend toward better according to treatment era (P = 0.063). In contrast, no obvious improvement of OS was observed in extranasal NKTCL (P = 0.43). The major inclusion criteria of the SMILE-P2 were met in 21% (10/47) of patients with extranasal NKTCL and 60% (188/311) of those with nasal NKTCL (P < 0.001). Despite the advent of new treatments for ENKL, OS remains unfavorable in extranasal NKTCL. A more effective therapy is needed for extranasal NKTCL.
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http://dx.doi.org/10.1007/s00277-019-03689-9DOI Listing
July 2019

JSH practical guidelines for hematological malignancies, 2018: II. Lymphoma-9. Extranodal NK/T-cell lymphoma, nasal type (ENKL).

Int J Hematol 2019 Apr 28;109(4):371-376. Epub 2019 Feb 28.

Shimane University Hospital Innovative Cancer Center, 89-1 Enya-cho, Izumo, Shimane, 693-8501, Japan.

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http://dx.doi.org/10.1007/s12185-019-02609-xDOI Listing
April 2019

JSH practical guidelines for hematological malignancies, 2018: 7. Peripheral T-cell lymphoma (PTCL).

Int J Hematol 2019 Feb 22;109(2):137-140. Epub 2019 Jan 22.

Shimane University Hospital Innovative Cancer Center, 89-1 Enya-cho, Izumo, Shimane, 693-8501, Japan.

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http://dx.doi.org/10.1007/s12185-018-02589-4DOI Listing
February 2019

Outcomes after R-CHOP in patients with newly diagnosed advanced follicular lymphoma: a 10-year follow-up analysis of the JCOG0203 trial.

Lancet Haematol 2018 Nov;5(11):e520-e531

Department of Haematology, National Cancer Center Hospital East, Chiba, Japan.

Background: Standard treatment for untreated advanced-stage follicular lymphoma is rituximab plus chemotherapy. The incidence of histological transformation of follicular lymphoma has been reported only in heterogeneously treated populations and rarely with long-term follow-up. Additionally, the incidence of secondary malignancies after treatment, without high-dose therapy for follicular lymphoma, is largely unknown. The aim of our study was to assess progression-free survival, overall survival, incidence of secondary malignancies, and incidence of histological transformation in a 10-year follow-up analysis of the JCOG0203 trial.

Methods: In the phase 2-3 randomised JCOG0203 trial, previously untreated patients with stage III or IV indolent B-cell lymphoma, including grades 1-3 follicular lymphoma, from 44 hospital centres in Japan, were randomly assigned (1:1) by use of a minimisation method to receive six cycles of R-CHOP (rituximab [375 mg/m], given on day 1, plus cyclophosphamide [750 mg/m], doxorubicin [50 mg/m], vincristine [1·4 mg/m, capped at 2·0 mg] given intravenously on day 3, and oral prednisone [100 mg once daily on days 3-7]) every 3 weeks (R-CHOP-21) or every 2 weeks (enabled by mandatory granulocyte-colony stimulating factor administration once daily for 6 days, starting on day 8; R-CHOP-14) without rituximab maintenance. Age, bulky disease (nodal or extranodal mass ≥10 cm in diameter on CT), and institution were used as adjustment factors. Investigators enrolled participants, and assignment to trial groups was done with a computer-assisted randomisation allocation sequence that took place centrally at the Japan Clinical Oncology Group Data Center, without the intervention of investigators. Interventions were not masked for patients or investigators. Data were collected 10 years after enrolment of the last patient. The primary endpoint of the phase 3 part of the study was progression-free survival, and the primary endpoint of the phase 2 part of the study was the proportion of patients who achieved a complete response. Accrual was 4·5 years, and follow-up was 3 years after registration was closed. Data were updated on the cutoff date of Feb 28, 2017. Intention-to-treat analyses (ie, progression-free survival, overall survival, and incidence of secondary malignancies) were predefined, to be done at 10 years after the last patient was enrolled. An additional analysis of the incidence of histological transformation was defined 15 years after the protocol, on May 8, 2017, in a supplementary analysis plan, and assessed at 10 years after the last patient was enrolled. Follow-up is ongoing. This trial is registered with ClinicalTrials.gov, number NCT00147121.

Findings: Between Sept 1, 2002, and Feb 28, 2007, 300 patients were enrolled, and 149 (50%) were assigned to the R-CHOP-21 group and 151 (50%) were assigned to the R-CHOP-14 group. After eligibility was assessed, one patient was excluded from the R-CHOP-21 group. 10-year progression-free survival was not different between groups (R-CHOP-21 33%, 95% CI 25-41; R-CHOP-14 39%, 31-47; hazard ratio 0·89, 95% CI 0·67-1·17). In 248 patients with grade 1-3a follicular lymphoma, progression-free survival was 39% (33-45) at 8 years and 36% (30-42) at 10 years. The cumulative incidence of histological transformation was 3·2% (95% CI 1·5-6·0) at 5 years, 8·5% (5·4-12·4) at 8 years, and 9·3% (6·1-13·4) at 10 years after enrolment. At 10 years, the cumulative incidence of secondary malignancies was 8·1% (5·1-12·0) and the cumulative incidence of haematological secondary malignancies was 2·9% (1·3-5·5).

Interpretation: R-CHOP is a viable option for first-line treatment in patients with newly diagnosed advanced follicular lymphoma. Clinicians choosing a first-line treatment for patients with follicular lymphoma should be cautious of secondary malignancies caused by immunochemotherapy and severe complications of infectious diseases in the long-term follow-up-both of which could lead to death.

Funding: National Cancer Center and Ministry of Health, Labour and Welfare of Japan.
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http://dx.doi.org/10.1016/S2352-3026(18)30155-8DOI Listing
November 2018

Extranodal NK/T-cell lymphoma: Updates in biology and management strategies.

Best Pract Res Clin Haematol 2018 09 3;31(3):315-321. Epub 2018 Jul 3.

Department of Oncology/Hematology, Shimane University Hospital, Izumo, Japan.

Extranodal NK/T-cell lymphoma, nasal type (ENKL), is a rare lymphoma subtype of peripheral T/NK-cell lymphoma that is very common in East Asia and Latin America. Two-thirds of patients have localized disease in the nasal cavity or adjacent sites. Large retrospective studies have revealed the clinicopathologic features of ENKL patients, identified risk factors for short survival time, and developed prognostic models. Next-generation sequencing studies have provided a comprehensive list of recurrent mutations in ENKL. Since the early 2000s, disease-specific therapeutic approaches have been developed, and the standard of care for ENKL has markedly changed. Non-anthracycline-containing chemotherapy with or without radiotherapy is the current standard approach for ENKL treatment. Emerging therapies, including the use of immune checkpoint inhibitors, are being investigated.
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http://dx.doi.org/10.1016/j.beha.2018.07.002DOI Listing
September 2018

[Treatment of NK/T-cell lymphoma: current situations and prospectives].

Authors:
Motoko Yamaguchi

Rinsho Ketsueki 2018;59(5):588-593

Department of Hematology and Oncology, Mie University Graduate School of Medicine.

Prior to the 2000, patients with extranodal NK/T-cell lymphoma, nasal type (ENKL) were typically treated with anthracycline-containing chemotherapy, such as CHOP therapy, and the therapeutic outcomes were unsatisfactory. Since the early 2000s, next-generation therapies without anthracyclines have been developed and tested in clinical trials, markedly changing ENKL treatment. A retrospective, Next-Generation Therapy for NK/T-Cell Lymphoma in East Asia (NKEA) Part A, study in Japan investigated the current state of ENKL management. The results revealed that radiotherapy and dexamethasone, etoposide, ifosfamide, and carboplatin (RT-DeVIC) concurrent chemoradiotherapy was selected as the first-line therapy in 66% patients with localized ENKL, diagnosed between 2010 and 2013 in 31 institutes in Japan. The 5-year overall survival and progression-free survival rates in 150 patients treated with RT-DeVIC in clinical practice were 72% and 61%, respectively, confirming the results of an RT-DeVIC clinical trial. Furthermore, the NKEA study highlighted several limitations of current ENKL management strategies. Now is the time to explore effective therapies for ENKL beyond the current next-generation therapies. International cooperation, utilizing the strengths of each country's treatment protocols, will contribute to advancement in ENKL treatment.
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http://dx.doi.org/10.11406/rinketsu.59.588DOI Listing
May 2019

[Overview].

Authors:
Motoko Yamaguchi

Rinsho Ketsueki 2018;59(5):496

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http://dx.doi.org/10.11406/rinketsu.59.496DOI Listing
January 2018

Advances in the treatment of extranodal NK/T-cell lymphoma, nasal type.

Blood 2018 06 30;131(23):2528-2540. Epub 2018 Mar 30.

Department of Radiation Oncology, Cancer Institute Hospital of the Japanese Foundation for Cancer Research, Tokyo, Japan.

Extranodal natural killer/T-cell lymphoma, nasal type (ENKL) is a subtype of mature T- and natural killer cell lymphomas characterized by its association with Epstein-Barr virus and extranodal involvement. Although there is geographic variance in the frequency of ENKL, its clinical features are similar between Western countries and endemic areas, such as East Asia. Anthracycline-containing chemotherapy is not recommended to treat ENKL. No standard treatment has been established based on the results of randomized controlled trials. In patients with localized disease, radiotherapy is a core component of the recommended first-line therapy. Radiotherapy administered at 50 to 54 Gy, extended involved-site radiotherapy considering tumor invasiveness, and the use of intensity modulated radiation therapy or volumetric modulated arc therapy are associated with efficacy of radiotherapy. Although the use of concurrent chemoradiotherapy has been supported by the results of clinical trials, accumulating evidence supports the use of sequential chemoradiotherapy with non-anthracycline-containing regimens that include l-asparaginase and/or platinum anticancer agents. l-asparaginase-containing chemotherapy is a key component of first-line treatments for systemic ENKL. Hematopoietic stem cell transplantation is recommended as a front-line consolidation therapy for newly diagnosed advanced-stage ENKL. Newer agents including immune checkpoint inhibitors are being investigated for treating ENKL. In this modern ENKL treatment era, multidisciplinary efforts are needed to identify the best timing and sequencing of radiotherapy, l-asparaginase, platinum, newer agents, and hematopoietic stem cell transplantation.
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http://dx.doi.org/10.1182/blood-2017-12-791418DOI Listing
June 2018

Early disease progression in patients with localized natural killer/T-cell lymphoma treated with concurrent chemoradiotherapy.

Cancer Sci 2018 Jun 28;109(6):2056-2062. Epub 2018 Apr 28.

Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu, Japan.

Prognosis of patients with localized nasal extranodal natural killer/T-cell lymphoma, nasal type (ENKL) has been improved by non-anthracycline-containing treatments such as concurrent chemoradiotherapy (CCRT). However, some patients experience early disease progression. To clarify the clinical features and outcomes of these patients, data from 165 patients with localized nasal ENKL who were diagnosed between 2000 and 2013 at 31 institutes in Japan and who received radiotherapy with dexamethasone, etoposide, ifosfamide, and carboplatin (RT-DeVIC) were retrospectively analyzed. Progression of disease within 2 years after diagnosis (POD24) was used as the definition of early progression. An independent dataset of 60 patients with localized nasal ENKL who received CCRT at Samsung Medical Center was used in the validation analysis. POD24 was documented in 23% of patients who received RT-DeVIC and in 25% of patients in the validation cohort. Overall survival (OS) from risk-defining events of the POD24 group was inferior to that of the reference group in both cohorts (P < .00001). In the RT-DeVIC cohort, pretreatment elevated levels of serum soluble interleukin-2 receptor (sIL-2R), lactate dehydrogenase, C-reactive protein, and detectable Epstein-Barr virus DNA in peripheral blood were associated with POD24. In the validation cohort, no pretreatment clinical factor associated with POD24 was identified. Our study indicates that POD24 is a strong indicator of survival in localized ENKL, despite the different CCRT regimens adopted. In the treatment of localized nasal ENKL, POD24 is useful for identifying patients who have unmet medical needs.
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http://dx.doi.org/10.1111/cas.13597DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5989836PMC
June 2018

[Atypical hemolytic uremic syndrome with C3 p.I1157T missense mutation successfully treated with eculizumab].

Rinsho Ketsueki 2018;59(2):178-181

Department of Hematology and Oncology, Mie University Graduate School of Medicine.

A 23-year-old man from Mie Prefecture, Japan, with past and family history of hematuria was diagnosed with influenza A and admitted to our hospital on the following day because of hemoglobinuria. He was diagnosed with thrombotic microangiopathy and was suspected of having atypical hemolytic uremic syndrome (aHUS). C3 p.I1157T missense mutation, which we had previously reported in eight aHUS patients from six families in Mie Prefecture, was identified. The laboratory findings and symptoms of our patient promptly improved after administering eculizumab. Little information is available on abnormalities of the complement system in aHUS or on mutation-specific outcomes of eculizumab therapy. Eculizumab was effective for treating our aHUS patient with C3 p.I1157T missense mutation.
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http://dx.doi.org/10.11406/rinketsu.59.178DOI Listing
February 2019

Topics on the molecular pathogenesis and therapeutic approaches for T/NK-cell lymphoma.

Authors:
Motoko Yamaguchi

J Clin Exp Hematop 2017 ;57(3):85-86

Department of Hematology and Oncology, Mie University Graduate School of Medicine.

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http://dx.doi.org/10.3960/jslrt.57001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6144184PMC
October 2018

Current treatment approaches for NK/T-cell lymphoma.

J Clin Exp Hematop 2017 Dec 6;57(3):98-108. Epub 2017 Jul 6.

Department of Hematology and Oncology, Mie University Graduate School of Medicine.

Extranodal NK/T-cell lymphoma, nasal type (ENKL), is a form of lymphoma characterized by preferential extranodal involvement, Epstein-Barr virus (EBV) association, and geographic diversity in incidence. ENKL tumor cells express P-glycoprotein, which is related to multidrug resistance (MDR). This MDR phenomenon is thought to be the major reason why ENKL is resistant to anthracycline-containing chemotherapies and has led researchers to explore novel therapeutic strategies. Since the early 2000s, next-generation therapies, including upfront radiotherapy, chemotherapy, or concurrent chemoradiotherapy using non-MDR-related drugs, have markedly changed the management of ENKL. However, a recent large retrospective study in Japan revealed several limitations of next-generation therapies, in particular that they resulted in almost no improvement of early disease progression. This review will summarize the current management of ENKL, primarily based on clinical trial results, and provide clues for better future management.
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http://dx.doi.org/10.3960/jslrt.17018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6144191PMC
December 2017

Treatments and Outcomes of Patients With Extranodal Natural Killer/T-Cell Lymphoma Diagnosed Between 2000 and 2013: A Cooperative Study in Japan.

J Clin Oncol 2017 Jan 31;35(1):32-39. Epub 2016 Oct 31.

Motoko Yamaguchi, Kana Miyazaki, Noriko Ii, and Naoyuki Katayama, Mie University Graduate School of Medicine, Tsu; Ritsuro Suzuki, Shimane University Hospital, Izumo; Masahiko Oguchi and Kyoko Ueda, Cancer Institute Hospital of the Japanese Foundation for Cancer Research; Yukio Kobayashi and Jun Itami, National Cancer Center Hospital; Bungo Saito, Showa University School of Medicine, Tokyo; Naoko Asano, Nagano Prefectural Suzaka Hospital, Suzaka; Jun Amaki and Takeshi Akiba, Tokai University School of Medicine, Isehara; Takeshi Maeda and Satoshi Itasaka, Kurashiki Central Hospital, Kurashiki; Nobuko Kubota and Yoshihiro Saito, Saitama Cancer Center, Ina; Naoto Tomita, Yokohama City University Graduate School of Medicine, Yokohama; Nodoka Sekiguchi, Shinshu University School of Medicine, Matsumoto; Jun Takizawa, Niigata University Faculty of Medicine, Niigata; Tohru Murayama, Hyogo Cancer Center, Akashi; Toshihiko Ando, Saga University, Saga; Hideho Wada, Kawasaki Medical School, Kurashiki; Rie Hyo, Nagoya University Graduate School of Medicine, Nagoya; Yasuo Ejima, Kobe University, Kobe; and Masatoshi Hasegawa, Nara Medical University, Kashihara, Japan.

Purpose To elucidate the management and outcomes of patients with extranodal natural killer/T-cell lymphoma, nasal type (ENKL), who were diagnosed between 2000 and 2013 in Japan. Patients and Methods Data from 358 patients with ENKL diagnosed between 2000 and 2013 from 31 institutes were retrospectively analyzed. Results Patients' median age was 58 years, and 257 (72%) had localized disease. The most common first-line treatment was radiotherapy with dexamethasone, etoposide, ifosfamide, and carboplatin (RT-DeVIC) (66%) for localized ENKL and L-asparaginase-containing chemotherapy (30%) for advanced ENKL. With a median follow-up of 5.8 years, overall survival (OS) rates at 5 years for localized and advanced ENKL were 68% and 24%, respectively. The prognostic index of natural killer lymphoma was validated in our study, although only 4% of patients with localized ENKL were classified as high risk. With a median follow-up of 5.6 years, OS and progression-free survival at 5 years in the 150 patients who received RT-DeVIC in clinical practice were 72% (95% CI, 63% to 78%) and 61% (95% CI, 52% to 69%), respectively. Toxicities of RT-DeVIC were comparable to those in a previous trial. Multivariate analysis in patients with localized ENKL who received RT-DeVIC identified elevated soluble interleukin-2 receptor as an independent predictive factor for worse OS and progression-free survival (adjusted hazard ratios, 2.28 and 2.46; 95% CI, 1.24 to 4.23 and 1.42 to 4.28; P = .008 and .0014, respectively). Conclusion Favorable OS in response to new treatments was demonstrated in a large number of patients. Improved treatment approaches are needed for localized ENKL exhibiting elevated pretreatment soluble interleukin-2 receptor.
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http://dx.doi.org/10.1200/JCO.2016.68.1619DOI Listing
January 2017

MYD88, CD79B, and CARD11 gene mutations in CD5-positive diffuse large B-cell lymphoma.

Cancer 2017 04 4;123(7):1166-1173. Epub 2016 Dec 4.

Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu, Japan.

Background: CD5-positive (CD5 ) diffuse large B-cell lymphoma (DLBCL) is characterized by frequent central nervous system recurrence and a predominant activated B-cell-like nature. Primary DLBCL in sanctuary sites (DLBCL-SS) also demonstrates these features, and >70% of patients harbor myeloid differentiation primary response 88 (MYD88) (L265P) and CD79B mutations. The objective of the current study was to elucidate a possible relationship between CD5 DLBCL and DLBCL-SS.

Methods: MYD88, CD79B, CD79A, and caspase recruitment domain family member 11 (CARD11) mutations were examined in samples from 40 patients with CD5 DLBCL. Mutation analysis was performed by direct sequencing.

Results: MYD88 and CD79B mutations were detected in 33% (13 patients) and 38% (15 patients), respectively, of the 40 patients with CD5 DLBCL. Ten patients had these 2 gene mutations, and 1 had a CD79A mutation. One of 2 patients with testicular involvement had both MYD88 and CD79B mutations. The other patient had a MYD88 mutation alone. None of the 31 patients examined was found to have a CARD11 mutation. MYD88 and CD79B mutations were found to be associated with localized disease (P = .038 and P = .003, respectively). Primary extranodal lymphoma was associated with higher frequencies of mutations in MYD88 or both MYD88 and CD79B (P = .008 and P = .014, respectively). There was no significant difference in overall survival based on MYD88 and CD79B mutation status.

Conclusions: The incidence of MYD88 and CD79B mutations in patients with CD5 DLBCL is lower than that in patients with DLBCL-SS, suggesting that CD5 DLBCL is not the same disease as DLBCL-SS in terms of gene mutation status. CARD11 mutations are rare in patients with CD5 DLBCL. Cancer 2017;123:1166-1173. © 2016 American Cancer Society.
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http://dx.doi.org/10.1002/cncr.30404DOI Listing
April 2017

Expressions of SH3BP5, LMO3, and SNAP25 in diffuse large B-cell lymphoma cells and their association with clinical features.

Cancer Med 2016 08 17;5(8):1802-9. Epub 2016 May 17.

Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu, Japan.

Diffuse large B-cell lymphoma (DLBCL) is clinicopathologically and genetically heterogeneous with variable clinical outcomes. We previously identified signature genes overexpressed in CD5-positive (CD5(+) ) DLBCL, which is a poor prognostic subgroup of DLBCL. To elucidate the clinical significance of the protein expression of the signature genes overexpressed in CD5(+) DLBCL with regard to all DLBCL, not otherwise specified (NOS), 10 genes (SH3BP5, LMO3, SNAP25, SYT5, SV2C, CABP1, FGF1, FGFR2, NEUROD1, and SYN2) were selected and examined immunohistochemically with samples from 28 patients with DLBCL, NOS. Only three protein expressions, SH3BP5, LMO3, and SNAP25, were detected in DLBCL cells and then analyzed further with samples from 187 patients with DLBCL, NOS. The SH3BP5, LMO3, and SNAP25 proteins were expressed in 60% (103/173), 34% (59/175), and 46% (77/168) of DLBCL patients, respectively. These protein expressions were associated with CD5 expression, and only SH3BP5 was frequently expressed in activated B-cell-like DLBCL (P = 0.046). Compared to the SH3BP5-negative group, the SH3BP5(+) group was correlated with elderly onset (>60 years, P = 0.0096) and advanced-stage disease (stage III/IV, P = 0.037). The LMO3(+) group showed a worse performance status (>1, P = 0.0004). The SH3BP5(+) group and the LMO3(+) group had significantly worse overall survival than the negative groups (P = 0.030, 0.034; respectively) for the entire group. In a subgroup analysis of patients treated with rituximab-containing chemotherapy, there was no significant difference between groups. To the best of our knowledge, this is the first report showing the protein expressions of SH3BP5, LMO3, and SNAP25 in DLBCL cells and their clinical significance in patients with DLBCL. The SH3BP5 and LMO3 protein expressions are associated with the baseline clinical characteristics of DLBCL.
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http://dx.doi.org/10.1002/cam4.753DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4873606PMC
August 2016

[Relapse in the nasal cavity of a patient with extranodal NK/T-cell lymphoma initially presenting as plantar subcutaneous tumor].

Rinsho Ketsueki 2015 Aug;56(8):1076-81

Department of Haematology and Oncology, Mie University Graduate School of Medicine.

A 36-year-old woman complained of a mass on the sole of her foot in February 200X. She was diagnosed with extranodal NK/T-cell lymphoma, nasal type (ENKL) by skin biopsy. Because the lesion was localized on the subcutaneous tissue of the sole, she was treated with RT/2/3DeVIC, resulting in a complete response (CR). In March of the following year, PET/CT showed significant uptake and mucosal thickening in the right nasal cavity, and a mucosal biopsy confirmed ENKL infiltration. Because the lesion was localized in the nasal cavity, she was re-treated with RT/2/3DeVIC, with a focus on local control, and she achieved a second CR. She subsequently received allogeneic hematopoietic stem cell transplantation in the hope of preventing systemic relapse. She has remained in CR for four years since the transplantation. Our case suggests that allogeneic hematopoietic stem cell transplantation to be a potentially promising approach to curative treatment for recurrent ENKL in younger patients. As nasal lesions may subsequently appear during the course of primary non-nasal ENKL, ongoing meticulous evaluation for nasal lesions is important.
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http://dx.doi.org/10.11406/rinketsu.56.1076DOI Listing
August 2015

[Development of new treatments for extranodal NK/T-cell lymphoma in Japan].

Authors:
Motoko Yamaguchi

Rinsho Ketsueki 2015 Jun;56(6):639-44

Department of Hematology and Oncology, Mie University Graduate School of Medicine.

Extranodal NK/T-cell lymphoma, nasal type (ENKL), accounts for less than 3% of malignant lymphomas in Japan. Based on the results of prospective clinical trials, ENKL treatment has dramatically improved during the last decade in Japan. The Lymphoma Study Group of the Japan Clinical Oncology Group (JCOG) conducted a phase I/II study (JCOG0211) of concurrent chemoradiotherapy for newly-diagnosed, localized ENKL. The trial showed an excellent 5-year overall survival rate (70%) and acceptable toxicity of RT-2/3DeVIC. The NK-cell Tumor Study Group in Japan, together with Asian collaborators, conducted clinical trials (SMILE-PI & PII) of SMILE chemotherapy for patients with newly-diagnosed stage IV, or relapsed/refractory ENKL. The overall response rate for 2 cycles of SMILE in 38 evaluated patients was 79%. The 2013 Japanese Society of Hematology guidelines recommend RT-2/3DeVIC for the treatment of newly-diagnosed ENKL of stage IE and contiguous stage IIE with cervical node involvement. For other ENKL, SMILE or other L-asparaginase-containing chemotherapies are recommended. A large retrospective study evaluating the efficacy and toxicity of these new treatments in clinical practice is currently underway in Japan. Close cooperation between radiation oncologists and international collaboration will be the key factors in developing better first-line treatments for ENKL.
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http://dx.doi.org/10.11406/rinketsu.56.639DOI Listing
June 2015

Gene expression profiling of diffuse large B-Cell lymphomas supervised by CD5 expression.

Int J Hematol 2015 Aug 26;102(2):188-94. Epub 2015 May 26.

Department of Hematology and Oncology, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie, 514-8507, Japan,

CD5-positive (CD5(+)) diffuse large B-cell lymphoma (DLBCL) has a poor prognosis and high incidence of central nervous system (CNS) relapse, even in the rituximab era. To determine the gene expression profile of CD5(+) DLBCL, total RNA from 90 patients with DLBCL, including 33 CD5(+) DLBCL and 57 CD5-negative (CD5(-)) DLBCL patients, was examined using Agilent human oligo microarrays. These cases were separated into 78 activated B-cell-like (ABC) DLBCLs and 12 germinal center B-cell-like (GCB) DLBCLs. All cases of CD5(+) DLBCL were classified as ABC DLBCLs. The classifier based on gene expression used in a supervised analysis correctly identified CD5 expression in the DLBCL and ABC DLBCL samples. The gene most relevant to CD5 expression was SH3BP5. Enriched GO categories in the CD5(+) ABC DLBCL signature gene set included multicellular organismal signaling, transmission of nerve impulse, and synaptic transmission. The present study, which includes the largest reported number of patients with CD5(+) DLBCL, confirmed that most CD5(+) DLBCLs are ABC DLBCLs, suggesting that therapeutic strategies for ABC DLBCL may be effective for the treatment of CD5(+) DLBCL. Our CD5(+) ABC DLBCL signature gene set may provide insights into the cause of the high frequency of CNS relapse in CD5(+) DLBCL.
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http://dx.doi.org/10.1007/s12185-015-1812-2DOI Listing
August 2015

[Successful treatment of Bing-Neel syndrome using combination therapy with fludarabine and rituximab].

Rinsho Ketsueki 2014 Dec;55(12):2423-8

Department of Hematology and Oncology, Mie University Graduate School of Medicine.

Bing-Neel syndrome is known as Waldenström's macroglobulinemia with central nervous system infiltration by neoplastic lymphoplasmacytoid and plasma cells. A 74-year-old man was admitted because of progressive cognitive impairment. Serum immunoelectrophoresis showed a monoclonal IgM-kappa component. Bone marrow aspiration revealed 59% small lymphocytes showing plasmacytoid differentiation. Bone marrow flow cytometry disclosed a population of kappa light-chain positive lymphoid cells expressing CD19, CD20, CD38, and CD138. Magnetic resonance imaging of the brain demonstrated gadolinium-enhancement in the right temporo-parieto-occipital meninges with sulcal enhancement. Cerebrospinal fluid cytology showed a population of lymphoplasmacytoid cells, positive for CD19, CD20, CD25, and kappa light-chain. Based on these findings, Bing-Neel syndrome was diagnosed. Although combination chemotherapy consisting of intrathecal methotrexate and oral cyclophosphamide was started, his symptoms continued to worsen. Then, we initiated treatment with a regimen consisting of fludarabine/rituximab (FR). After 6 courses of this FR regimen, a complete remission was achieved. Our case suggests the FR regimen to potentially be an effective treatment option for Bing-Neel syndrome of the scattered type.
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http://dx.doi.org/10.11406/rinketsu.55.2423DOI Listing
December 2014

Prognostic biomarkers in patients with localized natural killer/T-cell lymphoma treated with concurrent chemoradiotherapy.

Cancer Sci 2014 Nov 4;105(11):1435-41. Epub 2014 Oct 4.

Department of Hematology and Oncology, Mie University Graduate School of Medicine, Tsu, Japan.

Concurrent chemoradiotherapy has become one of the standard management approaches for newly diagnosed localized nasal natural killer (NK)/T-cell lymphoma (NKTCL). Few data are available on the prognostic biomarkers of NKTCL among patients treated with concurrent chemoradiotherapy. To evaluate the prognostic significance of immunophenotypic biomarkers for patients treated with concurrent chemoradiotherapy, latent membrane protein 1 (LMP1), cutaneous lymphocyte antigen (CLA) and cell origin were examined in samples from 32 patients who were enrolled in the Japan Clinical Oncology Group 0211 trial and treated with concurrent chemoradiotherapy. LMP1 and CLA were positive in 66% (19/29) and 29% (9/31) of the cases examined, respectively. The median follow-up duration was 68 months (range, 61-94). The patients with LMP1-positive tumors showed a better overall survival (OS) than the patients with LMP1-negative tumors (hazard ratio, 0.240; 95% confidence interval [CI], 0.057-1.013; 80% CI, 0.093-0.615; P = 0.035). All five patients with LMP1-negative tumors who experienced disease progression died of lymphoma, and both patients with local failure had LMP1-negative tumors. There was no significant difference in OS according to CLA expression. A total of 27 (84%) cases were of NK-cell origin, two were of αβ T-cell origin and three were of γδ T-cell origin. In contrast to those with tumors of NK-cell origin, all five patients with NKTCL of T-cell origin were alive without relapse at the last follow up. Our results indicate that LMP1 expression is a favorable prognostic marker and suggest that a T-cell origin of the tumor may be a favorable prognostic marker for patients with localized NKTCL treated with concurrent chemoradiotherapy.
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http://dx.doi.org/10.1111/cas.12526DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4462380PMC
November 2014

[T/NK-cell Lymphoma].

Authors:
Motoko Yamaguchi

Gan To Kagaku Ryoho 2014 May;41(5):576-9

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May 2014
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