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国立がん研究センター 中央病院

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Department of Hematology

Kensei Tobinai, Yukio Kobayashi, Dai Maruyama, Tatsuya Suzuki, Wataru Munakata, Suguru Fukuhara, Shinichi Makita, Nobuhiko Yamauchi, Kousuke Toyoda

Introduction

We are focusing on the diagnosis and treatment of hematological malignancies. In the past, our Department introduced several novel disease entities, including adult T-cell leukemialymphoma (ATL) (J Clin Oncol 2009; 27:453-9) and angioimmunoblastic T-cell lymphoma (Blood 1988; 72:1000-6). Our department is one of the leading hematology-oncology centers in the world, especially for lymphoid malignancies.

Routine activities

The number of patients with newly diagnosed hematological malignancies in the Division increased annually from 1997 to 2004, and then stabilized (Table 1). The diseases we treat are leukemia, MDS, lymphoma, and multiple myeloma. These diseases in a certain status require hematopoietic stem cell transplantation (HSCT), therefore, our Department is united with the Department of HSCT, and when necessary, HSCTs are provided by the HSCT Department. Such occasions include allogeneic HSCT against high risk AML, salvage autologous HSCT against lymphoma, and consolidative autologous HSCT against untreated multiple myeloma.

We hold a weekly case conference, where a summary of each hospitalized- or out-patient is presented. An educational cytology conference is held weekly for young doctors. Newly diagnosed lymphoma cases are presented at a weekly lymphoma case conference, where oncologists, pathologists, radiologists, and radiation oncologists discuss diagnosis and treatment plans. We also participate in weekly HSCT conferences, which deal with all HSCT cases.

In addition to patient care in the ward, our daily activities include management of hematology clinics and a diagnostic laboratory to perform bone marrow and peripheral blood microscopic examination, and flow cytometric and moleculargenetic analyses. Five staff physicians, three chief residents, and two to five rotating residents are involved in these routine activities.

Research activities

In addition to immunophenotypic analyses, molecular diagnosis is routinely performed, using polymerase chain reaction (PCR) and fluorescence in-situ hybridization (FISH) techniques for the detection of t(8;14), t(14;18), t(11;18), t(9;22), t(8;21), t(15;17), Flt3-ITD and so on. Our recent research has focused on indolent B-cell non-Hodgkin lymphoma (B-NHL). Clinical as well as molecular and cytogenetic analyses of ocular adnexal mucosaassociated lymphoid tissue (MALT) lymphoma cases led to the discovery of a new tumor suppressor gene deleted at 6q23; we identified the A20 gene as a tumor suppressor gene in various B-cell malignancies (Nature 2009; 459:712-6). In 2015, we initiated quantitative PCR assay for detection of MyD88 gene. These genes are involved in NFκB signaling and we assume that these markers will serve as a sensitivity test when using BCR inhibitors in B-cell malignancies.

We have constructed a tumor sample banking system, collecting the rest of the samples taken as routine diagnostic procedures. The samples' DNA and RNAs are extracted and reserved for future use.

This year, we authored or coauthored 22 original articles related to hematological malignancies.

Clinical trials

In 2015, we conducted 41 new-agent studies, including 18 international ones (Table 2). The number is still increasing including domestic studies. Almost all the new agents against hematological malignancies in Japan have been evaluated in our department, and a substantial number of them have been approved by the Pharmaceuticals and Medical Devices Agency (PMDA) in Japan.

Various phase I and II trials are ongoing on T-cell malignancies. The agents include mogamulizumab, lenalidomide, romidepsin, pralatrexate, forodesine, darinaparsin, chidamide, and denileukin diftitox. Some of the agents are being evaluated in international studies. For indolent ATL, we are evaluating interferon-alfa and AZT, as a phase III study (JCOG1111).

With the completion of the phase I study of oligopeptide vaccine OCV-501 against WT1 protein in AML cells to keep cases in complete remission, a randomized phase II trial is ongoing to evaluate the efficacy. The agent was developed in Japan, and is the first study against hematological malignancies aiming for approval by the PMDA.

For treatment of B-cell malignancies, patient enrolment into a phase III trial for newly diagnosed, diffuse large B-cell lymphoma (DLBCL) (JCOG0601) was completed. In this trial, a dose-intense schedule of rituximab was compared with that of a standard 3-weekly regimen. We also completed patient enrolment into phase II studies of rituximabincorporating dose-intensified chemotherapy regimens for high-risk, untreated DLBCL (JCOG0908), and untreated MCL (JCOG0406), using high-dose chemotherapy with autologous HSCT. For symptomatic multiple myeloma patients ineligible for HSCT, we are conducting a randomized phase II trial to find a more suitable combination regimen of bortezomib, melphalan and prednisolone (JCOG1105).

Education

We trained three chief residents and seven hematology residents following our residency program. We also trained five rotating medical oncology residents.

We are devoted to publication of guidelines for hematological malignancies, and act as lecturers or nominees in various hematology and oncology societies.

Future prospects

We have attracted and educated physicians in trainee programs. Many graduates from our program are actively engaged in hematology and oncology societies. We are steering JCOG and JALSG, which are major cooperative study groups for hematological malignancies in Japan. More involvement in international studies is necessary, and more cooperative studies with other departments such as the Department of Pathology and Clinical Laboratories in NCCH and Division of Hematological Malignancy in NCCRI. and Division of Hematological Malignancy in the National Cancer Center Research Institute.

Table 1. The number of patients with newly diagnosed hematologic malignancies who were managed in the Hematology Division


Table 2. Clinical trials for new agent development


Table 3. Clinical studies of Cooperative Group

List of papers published in 2015

Journal

  1. Kamiyama Y, Kobayashi Y, Fukuhara S, Morikawa N, Munakata W, Miyagi Maeshima A, Maruyama D, Kim SW, Watanabe T, Terauchi T, Muramatsu Y, Tobinai K. Incidental detection of malignant lymphoma in subjects in a cancer surveillance programme. Br J Haematol, 169:138-142, 2015
  2. Suzuki K, Ogura M, Abe Y, Suzuki T, Tobinai K, Ando K, Taniwaki M, Maruyama D, Kojima M, Kuroda J, Achira M, Iizuka K. Phase 1 study in Japan of siltuximab, an anti-IL-6 monoclonal antibody, in relapsed/refractory multiple myeloma. Int J Hematol, 101:286-294, 2015
  3. Ishida T, Jo T, Takemoto S, Suzushima H, Uozumi K, Yamamoto K, Uike N, Saburi Y, Nosaka K, Utsunomiya A, Tobinai K, Fujiwara H, Ishitsuka K, Yoshida S, Taira N, Moriuchi Y, Imada K, Miyamoto T, Akinaga S, Tomonaga M, Ueda R. Dose-intensified chemotherapy alone or in combination with mogamulizumab in newly diagnosed aggressive adult T-cell leukaemia-lymphoma: a randomized phase II study. Br J Haematol, 169:672-682, 2015
  4. Tateishi U, Tatsumi M, Terauchi T, Ando K, Niitsu N, Kim WS, Suh C, Ogura M, Tobinai K. Prognostic significance of metabolic tumor burden by positron emission tomography/computed tomography in patients with relapsed/refractory diffuse large B-cell lymphoma. Cancer Sci, 106:186-193, 2015
  5. Maeshima AM, Taniguchi H, Tanioka K, Kitahara H, Miyamoto K, Fukuhara S, Munakata W, Suzuki T, Maruyama D, Kobayashi Y, Tobinai K, Kushima R. Clinicopathological characteristics of follicular lymphoma with peripheral blood involvement. Leuk Lymphoma, 56:2000-2004, 2015
  6. Nakaseko C, Takahashi N, Ishizawa K, Kobayashi Y, Ohashi K, Nakagawa Y, Yamamoto K, Miyamura K, Taniwaki M, Okada M, Kawaguchi T, Shibata A, Fujii Y, Ono C, Ohnishi K. A phase 1/2 study of bosutinib in Japanese adults with Philadelphia chromosome-positive chronic myeloid leukemia. Int J Hematol, 101:154-164, 2015
  7. Kataoka K, Nagata Y, Kitanaka A, Shiraishi Y, Shimamura T, Yasunaga J, Totoki Y, Chiba K, Sato-Otsubo A, Nagae G, Ishii R, Muto S, Kotani S, Watatani Y, Takeda J, Sanada M, Tanaka H, Suzuki H, Sato Y, Shiozawa Y, Yoshizato T, Yoshida K, Makishima H, Iwanaga M, Ma G, Nosaka K, Hishizawa M, Itonaga H, Imaizumi Y, Munakata W, Ogasawara H, Sato T, Sasai K, Muramoto K, Penova M, Kawaguchi T, Nakamura H, Hama N, Shide K, Kubuki Y, Hidaka T, Kameda T, Nakamaki T, Ishiyama K, Miyawaki S, Yoon SS, Tobinai K, Miyazaki Y, Takaori-Kondo A, Matsuda F, Takeuchi K, Nureki O, Aburatani H, Watanabe T, Shibata T, Matsuoka M, Miyano S, Shimoda K, Ogawa S. Integrated molecular analysis of adult T cell leukemia/lymphoma. Nat Genet, 47:1304-1315, 2015
  8. Narita T, Inagaki A, Kobayashi T, Kuroda Y, Fukushima T, Nezu M, Fuchida S, Sakai H, Sekiguchi N, Sugiura I, Maeda Y, Takamatsu H, Tsukamoto N, Maruyama D, Kubota Y, Kojima M, Sunami K, Ono T, Ri M, Tobinai K, Iida S. t(14;16)-positive multiple myeloma shows negativity for CD56 expression and unfavorable outcome even in the era of novel drugs. Blood Cancer J, 5:e285, 2015
  9. Ohmoto A, Maeshima AM, Taniguchi H, Tanioka K, Makita S, Kitahara H, Fukuhara S, Munakata W, Suzuki T, Maruyama D, Kobayashi Y, Tobinai K. Histopathological analysis of B-cell non-Hodgkin lymphomas without light chain restriction by using flow cytometry. Leuk Lymphoma, 56:3301-3305, 2015
  10. Maeshima AM, Taniguchi H, Nomoto J, Makita S, Kitahara H, Fukuhara S, Munakata W, Suzuki T, Maruyama D, Kobayashi Y, Tobinai K. Clinicopathological features of classical Hodgkin lymphoma in patients ≥ 40 years old, with special reference to composite cases. Jpn J Clin Oncol, 45:921-928, 2015
  11. Matsue K, Iwasaki H, Chou T, Tobinai K, Sunami K, Ogawa Y, Kurihara M, Midorikawa S, Zaki M, Doerr T, Iida S. Pomalidomide alone or in combination with dexamethasone in Japanese patients with refractory or relapsed and refractory multiple myeloma. Cancer Sci, 106:1561-1567, 2015
  12. Miyagi Maeshima A, Taniguchi H, Makita S, Kitahara H, Miyamoto K, Fukuhara S, Munakata W, Suzuki T, Maruyama D, Kobayashi Y, Tobinai K. Histopathological Characteristics of Lymphomas in the Upper Aerodigestive Tract. A Single-Institute Study in Japan. J Clin Exp Hematop, 55:7-11, 2015
  13. Ogura M, Uchida T, Terui Y, Hayakawa F, Kobayashi Y, Taniwaki M, Takamatsu Y, Naoe T, Tobinai K, Munakata W, Yamauchi T, Kageyama A, Yuasa M, Motoyama M, Tsunoda T, Hatake K. Phase I study of OPB-51602, an oral inhibitor of signal transducer and activator of transcription 3, in patients with relapsed/ refractory hematological malignancies. Cancer Sci, 106:896-901, 2015
  14. Tanaka Y, Kobayashi Y, Maeshima AM, Oh SY, Nomoto J, Fukuhara S, Kitahara H, Munakata W, Suzuki T, Maruyama D, Tobinai K. Intravascular large B-cell lymphoma secondary to lymphoplasmacytic lymphoma: a case report and review of literature with clonality analysis. Int J Clin Exp Pathol, 8:3339-3343, 2015
  15. Kusumoto S, Tanaka Y, Suzuki R, Watanabe T, Nakata M, Takasaki H, Fukushima N, Fukushima T, Moriuchi Y, Itoh K, Nosaka K, Choi I, Sawa M, Okamoto R, Tsujimura H, Uchida T, Suzuki S, Okamoto M, Takahashi T, Sugiura I, Onishi Y, Kohri M, Yoshida S, Sakai R, Kojima M, Takahashi H, Tomita A, Maruyama D, Atsuta Y, Tanaka E, Suzuki T, Kinoshita T, Ogura M, Mizokami M, Ueda R. Monitoring of Hepatitis B Virus (HBV) DNA and Risk of HBV Reactivation in B-Cell Lymphoma: A Prospective Observational Study. Clin Infect Dis, 61:719-729, 2015
  16. Saito H, Maruyama D, Maeshima AM, Makita S, Kitahara H, Miyamoto K, Fukuhara S, Munakata W, Suzuki T, Kobayashi Y, Taniguchi H, Tobinai K. Prolonged lymphocytopenia after bendamustine therapy in patients with relapsed or refractory indolent B-cell and mantle cell lymphoma. Blood Cancer J, 5:e362, 2015
  17. Kobayashi Y, Yamauchi T, Kiyoi H, Sakura T, Hata T, Ando K, Watabe A, Harada A, Taube T, Miyazaki Y, Naoe T. Phase I trial of volasertib, a Polo-like kinase inhibitor, in Japanese patients with acute myeloid leukemia. Cancer Sci, 106:1590-1595, 2015
  18. Ito J, Yoshida A, Maeshima AM, Nakagawa K, Watanabe S, Kobayashi Y, Fukuhara S, Tsuta K. Concurrent thymoma, thymic carcinoma, and T lymphoblastic leukemia/lymphoma in an anterior mediastinal mass. Pathol Res Pract, 211:693-696, 2015