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Intravascular large B-cell lymphoma (IVLBCL) is a unique type of extranodal lymphoma characterized by selective growth of tumor cells in small vessels without lymphadenopathy. Greater understanding of the molecular pathogenesis of IVLBCL is hampered by the paucity of lymphoma cells in biopsy specimens, creating a limitation in obtaining sufficient tumor materials. To uncover the genetic landscape of IVLBCL, we performed whole-exome sequencing (WES) of 21 patients with IVLBCL using plasma-derived cell-free DNA (cfDNA) (n = 18), patient-derived xenograft tumors (n = 4), and tumor DNA from bone marrow (BM) mononuclear cells (n = 2). The concentration of cfDNA in IVLBCL was significantly higher than that in diffuse large B-cell lymphoma (DLBCL) (P < .0001) and healthy donors (P = .0053), allowing us to perform WES; most mutations detected in BM tumor DNA were successfully captured in cfDNA and xenograft. IVLBCL showed a high frequency of genetic lesions characteristic of activated B-cell–type DLBCL, with the former showing conspicuously higher frequencies (compared with nodal DLBCL) of mutations in MYD88 (57%), CD79B (67%), SETD1B (57%), and HLA-B (57%). We also found that 8 IVLBCL (38%) harbored rearrangements of programmed cell death 1 ligand 1 and 2 (PD-L1/PD-L2) involving the 3′ untranslated region; such rearrangements are implicated in immune evasion via PD-L1/PD-L2 overexpression. Our data demonstrate the utility of cfDNA and imply important roles for immune evasion in IVLBCL pathogenesis and PD-1/PD-L1/PD-L2 blockade in therapeutics for IVLBCL.

Summary 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.

Introduction: Intravascular large B-cell lymphoma (IVLBCL) is a rare disease entity characterized by selective growth of lymphoma cells in the lumina of small vessels. IVLBCL has been listed in the WHO classification, which improves recognition of the disease. However, no standard therapy has been established based on the results of prospective studies. We previously reported promising efficacy of rituximab (R)-containing chemotherapy for IVLBCL (JCO 2008) and a high incidence of central nervous system (CNS) recurrence (25% at 3 y) after R-chemotherapy (Lancet Oncol 2009, Cancer Sci 2010). To explore a more effective first-line treatment, we conducted a phase 2 trial of R-CHOP combined with CNS prophylaxis including R-high-dose methotrexate (R-HDMTX) and intrathecal chemotherapy with MTX, cytarabine (Ara-C), and prednisolone (PSL) (IT). Methods: Major inclusion criteria were untreated, histologically confirmed IVLBCL, age 20-79 y, ECOG PS 0-3, and no apparent CNS involvement at diagnosis. Patients received 3 cycles of R-CHOP followed by 2 cycles of R-HDMTX (3.5 g/m2; 2 g/m2 for ≥70 y) every 2 weeks, and 3 additional cycles of R-CHOP. IT (MTX 15 mg, Ara-C 40 mg, PSL 10 mg) was performed twice during the first 3 cycles of R-CHOP and twice during the final 3 cycles of R-CHOP (4 times in total). If patients achieved complete response (CR), they were observed without any therapy until relapse or disease progression. The primary endpoint was 2-y progression-free survival (PFS), and secondary endpoints included 2-y overall survival (OS), CR rate, cumulative incidence of CNS recurrence at 2 y, patterns of progression, and adverse events. The threshold 2-y PFS was estimated to be 35%, with expected 2-y PFS estimated to be 60%. With a statistical power of 90% and a one-sided, type I error of 5%, a projected sample size of 37 was calculated in anticipation of 10% ineligible patients. The trial was registered in the UMIN Clinical Trials Registry (UMIN000005707). Results: 38 IVLBCL patients were enrolled between June 2011 and July 2016. One patient was found to be ineligible after completion of the protocol treatment due to a past history of lymphoma. The protocol treatment was completed in 34 (89%) of 38 patients. The diagnosis of IVLBCL was histologically confirmed by central pathological review in all enrolled patients. The baseline characteristics of the 37 eligible patients were: male sex, 16 (43%); median age, 66 (range 38-78) y; ECOG PS >1, 15 (41%); stage IV, 37 (100%); serum LDH >ULN, 36 (97%); WBC Conclusion: This phase 2 trial met its primary endpoint and showed favorable outcomes with a low cumulative incidence of CNS recurrence and acceptable toxicity profiles. These results indicate that R-CHOP combined with CNS prophylaxis including R-HDMTX and IT could be a reasonable treatment option for untreated IVLBCL without apparent CNS involvement at diagnosis. Disclosures Shimada: Takeda Pharmaceutical: Honoraria; MSD: Research Funding; Otsuka Pharmaceutical: Research Funding; Janssen Pharmaceutical: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Eisai: Honoraria, Research Funding; Chugai Pharmaceutical: Consultancy, Honoraria; Kyowa Kirin: Honoraria, Research Funding; AstraZeneca: Honoraria. Yamaguchi:Ono Pharmaceutical: Research Funding; Teijin Pharma: Honoraria; MSD: Honoraria; Astrazeneca: Membership on an entity's Board of Directors or advisory committees; Sumitomo Dainippon Pharma: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Astellas Pharma: Research Funding; Sorrento: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Meiji Seika Kaisha: Honoraria; Kyowa Hakko Kirin: Honoraria, Research Funding; Eisai: Honoraria; Chugai: Honoraria, Research Funding. Atsuta:Chugai Pharmaceutical Co., Ltd.: Honoraria; Kyowa Kirin Co., Ltd: Honoraria; Mochida Pharmaceutical Co. Ltd: Honoraria; Janssen Paharmaceutical K.K.: Honoraria. Matsue:Celgene: Honoraria; Takeda Pharmaceutical Company Limited: Honoraria; Ono Pharmaceutical: Honoraria; Novartis Pharma K.K: Honoraria; Janssen Pharmaceutical K.K.: Honoraria. Kusumoto:Chugai Pharmaceutical Co., Ltd.: Consultancy, Honoraria, Research Funding; Kyowa Kirin Co., Ltd.: Honoraria, Research Funding. Nagai:Eisai: Honoraria, Research Funding; HUYA Bioscience International: Research Funding; AstraZeneca: Honoraria, Research Funding; Takeda Pharmaceutical: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen Pharmaceutical: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Zenyaku Kogyo: Honoraria, Research Funding; Sanofi: Honoraria; Otsuka Pharmaceutical: Research Funding; SymBio Pharmaceuticals Limited: Honoraria, Research Funding; Solasia Pharma K.K.: Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Kyowa Kirin: Honoraria, Research Funding; IQVIA: Research Funding; Chugai Pharmaceutical: Honoraria, Research Funding; MSD: Honoraria; Novartis Pharma: Honoraria; Mundi Pharma: Honoraria, Research Funding; Bayer Pharma: Honoraria, Research Funding; AbbVie: Research Funding. Fukuhara:Mundi: Honoraria; Celgene Corporation: Honoraria, Research Funding; Chugai Pharmaceutical Co., Ltd.: Honoraria; Eisai: Honoraria, Research Funding; Janssen Pharma: Honoraria; Kyowa-Hakko Kirin: Honoraria; Mochida: Honoraria; Nippon Shinkyaku: Honoraria; Ono Pharmaceutical Co., Ltd.: Honoraria; Takeda Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Zenyaku: Honoraria; AbbVie: Research Funding; Bayer: Research Funding; Gilead: Research Funding; Solasia Pharma: Research Funding. Miyazaki:Eisai: Honoraria; Chugai: Honoraria; Kyowa Hakko Kirin: Honoraria, Research Funding; Celgene: Honoraria; Ono Pharmaceutical: Research Funding; Astellas Pharma: Research Funding; Takeda: Honoraria; SymBio Pharmaceuticals: Honoraria; Nippon Shinyaku: Honoraria; Janssen Pharmaceutical: Honoraria. Okamoto:Kyowa Kirin Co., Ltd.: Other: Scholarship donation; Chugai Pharmaceutical Co., Ltd.: Other: Scholarship donation; Takeda Pharmaceutical Co., Ltd.: Other: Scholarship donation; Taiho Pharmaceutical Co., Ltd.: Other: Scholarship donation. Uchida:Eisai: Honoraria. Tsukasaki:Daiichi Sankyo: Consultancy; Kyowa Kirin: Honoraria; Huya: Consultancy, Honoraria, Research Funding; Byer: Research Funding; Mundi Pharma: Honoraria; Ono Pharmaceutical: Consultancy; Eisai: Research Funding; Chugai Pharmaceutical: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Masaki:Tanabe Mitsubishi: Research Funding; Taiho: Research Funding; Kyowa Kirin: Research Funding; Astellas Pharma: Research Funding; Chugai Pharmaceutical: Research Funding; Ono Pharmaceutical: Research Funding; Pfizer: Research Funding; Eisai: Research Funding; Taisho Toyama: Research Funding; Daiichi Sankyo: Research Funding; Teijin: Research Funding; Takeda Pharmaceutical: Research Funding. Kiyoi:Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Bristol-Myers Squibb: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Astellas Pharma Inc.: Honoraria, Research Funding; Takeda Pharmaceutical Co., Ltd.: Research Funding; Zenyaku Kogyo Co., Ltd.: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding; Otsuka Pharmaceutical Co.,Ltd.: Research Funding; FUJIFILM Corporation: Research Funding; Eisai Co., Ltd.: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; Pfizer Japan Inc.: Honoraria; Perseus Proteomics Inc.: Research Funding; Daiichi Sankyo Co., Ltd: Research Funding. Suzuki:Chugai Pharmaceutical Co.,Ltd.: Honoraria; Meiji Seika: Honoraria; Merck Sharp & Dohme: Honoraria; Takeda Pharmaceutical Co., Ltd.: Honoraria; Bristol-Myers Squibb: Honoraria; Kyowa Hakko Kirin: Honoraria; Celgene: Honoraria; Eisai: Honoraria; ONO Pharmaceutical Co., Ltd.: Honoraria; Janssen: Honoraria; AbbVie: Honoraria; Novartis: Honoraria.

A 40's year-old female patient with acute myeloblastic leukemia received high-dose cytarabine(HD-Ara-C)as her third induction therapy. Because the pharmacist in charge noticed on a prior interview that she had experienced a mild skin eruption similar to hand-foot syndrome(HFS)in the previous round oftherapy(idarubicin and cytarabine), heparinoid lotion and hypoallergenic soap were used to prevent HFS. However, HFS occurred on day 3, and further developed on day 6 to grade 3 with painful erythema, swelling, and paresthesia affecting the entire surface of both hands. We cared for her with moisturization, lifestyle guidance, rotation of steroid ointment, and occlusive dressing techniques according to a multidisciplinary team approach composed ofa hematologist, dermatologist, pharmacist, and nurse. Her symptoms resolved on day 40.

Introduction: We report the results of a prospective study of long-tern treatment with single-agent thalidomide in patients who had responded in a preceding trial of the use of thalidomide for relapsed/refractory myeloma. Patients and Methods: Nineteen patients were enrolled: 11 patients (57.9%) treated at a dosage of 100 mg/day; 2 patients (10.5%) at a dosage of 200 mg/day; 2 patients (10.5%) at a dosage of 300 mg/day; and 4 patients (21.1%) at a dosage of 400 mg/day. The median follow-up from the start of the preceding study was 3.0 years. At the time of entry to this study, 5 patients (26.3%) had partial response (PR), another 5 patients (26.3%) had a minimal response (MR), and the remaining 9 patients (47.4%) had shown no change (NC). Results: The cumulative MR rate was 78.9% (at the 32nd week) and the cumulative PR rate was 47.4% (at the 112th week). The median progression-free survival was 104 weeks and the median time to next treatment was 144 weeks. No patients experienced grade 4 or greater hematologic toxicity or grade 3 or greater non-hematologic toxicity. Conclusion: Long-term thalidomide maintenance therapy induced an increase in response rate, suppressed the progression to active myeloma without severe adverse events, and contributed to long survival with good activities of daily living.

To evaluate the role of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) in intravascular large B-cell lymphoma (IVLBCL), we retrospectively analyzed four consecutive IVLBCL patients receiving FDG-PET before treatment between May 2006 and November 2007. Patients were two men and two women (median age 62 years, range 54-76 years). All patients received bone marrow biopsies and random skin biopsies and two of the four patients underwent renal biopsy for diagnosis. Accuracy of FDG-PET for the detection of organ involvements was analyzed by comparing results of pathological findings. Concordant results with respect to bone marrow involvement were accurately obtained for two patients. Skin and renal involvements were undetectable by FDG-PET regardless of positive pathological findings. One patient with a false-negative FDG-PET result showed fewer lymphoma cells in the bone marrow specimen than patients with concordant FDG-PET results. These results suggest false-negative results for some types of organ involvement. Careful interpretation of the results of FDG-PET in IVLBCL is thus required.

The cyclin-dependent kinase inhibitor p57(KIP2) is thought to be a potential tumor suppressor gene (TSG). The present study examines this possibility. We found that the expression of p57(KIP2) gene is absent in various hematological cell lines. Exposing cell lines to the DNA demethylating agent 5-aza-2'-deoxycytidine restored p57(KIP2) gene expression. Bisulfite sequencing analysis of its promoter region showed that p57(KIP2) DNA was completely methylated in cell lines that did not express the p57(KIP2) gene. Thus, DNA methylation of its promoter might lead to inactivation of the p57(KIP2) gene. DNA methylation of this region is thought to be an aberrant alteration, since DNA was not methylated in normal peripheral blood mononuclear cells or in reactive lymphadenitis. Methylation-specific polymerase chain reaction analysis found frequent DNA methylation of the p57(KIP2) gene in primary diffuse large B-cell lymphoma (54.9%) and in follicular lymphoma (44.0%), but methylation was infrequent in myelodysplastic syndrome and adult T-cell leukemia (3.0% and 2.0%, respectively). These findings directly indicate that the profile of the p57(KIP2) gene corresponds to that of a TSG.

Introduction The prognosis of Philadelphia chromosome positive acute lymphoblastic leukemia (Ph + ALL) has been dramatically improved since the introduction of tyrosine kinase inhibitors (TKIs). Although allogeneic hematopoietic cell transplantation (allo-HCT) is a major treatment option, the role of autologous peripheral blood stem cell transplantation (auto-PBSCT) has been reconsidered, especially in patients who achieved early molecular remission. Methods and analysis This is a multicenter exploratory study for Ph + ALL patients aged between 55 and 70 years who achieved complete molecular remission within 3 cycles of chemotherapy. The target sample size is 5, and the registration period is 2 years. The primary endpoint is Day100- mortality after transplantation, and the secondary endpoints are survival, relapse rate, nonrelapse mortality, and adverse events.This study is divided into 3 phases: peripheral blood stem cell harvest, transplantation, and maintenance. Chemomobilization is performed using a combination of cyclophosphamide (CPM), doxorubicin, vincristine (VCR), and prednisolone (PSL). As a preparative regimen, the LEED regimen is used, which consists of melphalan, CPM, etoposide, and dexamethasone. Twelve cycles of maintenance therapy using a combination of VCR, PSL, and dasatinib are performed.In association with relapse, the minimal residual disease (MRD) of BCR-ABL chimeric gene and T-cell subsets are analyzed both before and after auto-PBSCT. Ethics and dissemination The protocol was approved by the institutional review board of Nagoya University Hospital and all the participating hospitals. Written informed consent was obtained from all patients before registration, in accordance with the Declaration of Helsinki. Results of the study will be disseminated via publications in peer-reviewed journals. Trial registration Trial registration number UMIN000026445.