Department of Hematology

Kensei Tobinai, Yukio Kobayashi, Dai Maruyama, Tatsuya Suzuki, Wataru Munakata, Suguru Fukuhara, Shinichi Makita, Kosuke Toyoda, Nobuhiko Yamauchi, Tomotaka Suzuki, Sayako Yuda

Introduction

The Department of Hematology is united with the Department of Hematopoietic Stem Cell Transplantation (HSCT), and the research and clinical activities in the Department of Hematology are devoted to the diagnosis and treatment of hematological malignancies. In the past, our department introduced novel disease entities, including adult T-cell leukemia-lymphoma (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.

Our team and what we do

The number of patients with newly diagnosed hematologic malignancies in our department 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 Department of HSCT. Such occasions include allogeneic HSCT against high risk AML, salvage autologous HSCT against malignant 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 molecular-genetic analyses. Six staff physicians, four 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 mucosa-associated lymphoid tissue (MALT) lymphoma cases led to the discovery of a new tumor suppressor gene deleted at 6q23; we identified A20 gene as a tumor suppressor gene in various B-cell malignancies (Nature 2009; 459:712-6). In 2016, we stated targeted exon sequence for B-cell and myeloid malignancies. The B-cell panel includes genes in NFkB 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 29 articles related to hematological malignancies including one review article.

Clinical trials

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

In 2016, we conducted 44 new-agent studies, including 8 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 lenalidomide, romidepsin, 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 (JCOG 1111).

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, a phase III trial for newly diagnosed, diffuse large B-cell lymphoma (DLBCL) (JCOG 0601) was completed. In this trial, a dose-intense schedule of rituximab was compared with that of a standard three-weekly regimen. We also completed patient enrolment into phase II studies of rituximab-incorporating dose-intensified chemotherapy for high-risk, untreated DLBCL (JCOG 0908), 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 (JCOG 1105).

Education

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

We are devoted to publication of guidelines in 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 programs 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 (Table 3). More involvement in international studies is necessary, and more cooperative studies with other departments are awaited, including the Pathology Department and the Division of Hematological Malignancy in the UK NCRI. Under a new department head's initiative, we hope that our department will further flourish in the coming year.

Table 2. Clinical trials for new agent development

Table 3. Cooperative group studies

List of papers published in 2016

Journal

1.Tobinai K, Ogura M, Ishizawa K, Suzuki T, Munakata W, Uchida T, Aoki T, Morishita T, Ushijima Y, Takahara S. Safety and tolerability of ibrutinib monotherapy in Japanese patients with relapsed/refractory B cell malignancies. Int J Hematol, 103:86-94, 2016

2.Ogura M, Imaizumi Y, Uike N, Asou N, Utsunomiya A, Uchida T, Aoki T, Tsukasaki K, Taguchi J, Choi I, Maruyama D, Nosaka K, Chen N, Midorikawa S, Ohtsu T, Tobinai K. Lenalidomide in relapsed adult T-cell leukaemia-lymphoma or peripheral T-cell lymphoma (ATLL-001): a phase 1, multicentre, dose-escalation study. Lancet Haematol, 3:e107-e118, 2016

3.Okuma HS, Kobayashi Y, Makita S, Kitahara H, Fukuhara S, Munakata W, Suzuki T, Maruyama D, Tobinai K. Disseminated herpes zoster infection initially presenting with abdominal pain in patients with lymphoma undergoing conventional chemotherapy: A report of three cases. Oncol Lett, 12:809-814, 2016

4.Ueda R, Maruyama D, Nomoto J, Maeshima AM, Fukuhara S, Kitahara H, Miyamoto K, Munakata W, Suzuki T, Taniguchi H, Kobayashi Y, Tobinai K. FUS-ERG gene fusion in isolated myeloid sarcoma showing uncommon clinical features. Oxf Med Case Reports, 2016:4-8, 2016

5.Kataoka K, Shiraishi Y, Takeda Y, Sakata S, Matsumoto M, Nagano S, Maeda T, Nagata Y, Kitanaka A, Mizuno S, Tanaka H, Chiba K, Ito S, Watatani Y, Kakiuchi N, Suzuki H, Yoshizato T, Yoshida K, Sanada M, Itonaga H, Imaizumi Y, Totoki Y, Munakata W, Nakamura H, Hama N, Shide K, Kubuki Y, Hidaka T, Kameda T, Masuda K, Minato N, Kashiwase K, Izutsu K, Takaori-Kondo A, Miyazaki Y, Takahashi S, Shibata T, Kawamoto H, Akatsuka Y, Shimoda K, Takeuchi K, Seya T, Miyano S, Ogawa S. Aberrant PD-L1 expression through 3'-UTR disruption in multiple cancers. Nature, 534:402-406, 2016

6.Watanabe T, Tobinai K, Matsumoto M, Suzuki K, Sunami K, Ishida T, Ando K, Chou T, Ozaki S, Taniwaki M, Uike N, Shibayama H, Hatake K, Izutsu K, Ishikawa T, Shumiya Y, Kashihara T, Iida S. A phase 1/2 study of carfilzomib in Japanese patients with relapsed and/or refractory multiple myeloma. Br J Haematol, 172:745-756, 2016

7.Fukushima R, Kobayashi Y, Fukuhara S, Miyamoto Ki, Munakata W, Maruyama D, Kim S-W, Watanabe T, Taniguchi H, Maeshima A, Tobinai K. A retrospective analysis of combination chemotherapy consisting cyclophosphamide, vincristine, prednisolone and procarbazine (C-MOPP) for pretreated aggressive non-Hodgkin lymphoma. J Chemother, 28:116-122, 2016

8.Makita S, Fuji S, Takano K, Tanaka T, Inoue Y, Ito R, Ito A, Hayashi Y, Tajima K, Okinaka K, Kurosawa S, Kim S-W, Yamashita T, Tanosaki R, Tobinai K, Fukuda T. Clinical Outcomes after Allogeneic Stem Cell Transplantation for Adult Lymphoblastic Lymphoma. J Clin Exp Hematop, 56:28-33, 2016

9.Nagata Y, Kontani K, Enami T, Kataoka K, Ishii R, Totoki Y, Kataoka TR, Hirata M, Aoki K, Nakano K, Kitanaka A, Sakata-Yanagimoto M, Egami S, Shiraishi Y, Chiba K, Tanaka H, Shiozawa Y, Yoshizato T, Suzuki H, Kon A, Yoshida K, Sato Y, Sato-Otsubo A, Sanada M, Munakata W, Nakamura H, Hama N, Miyano S, Nureki O, Shibata T, Haga H, Shimoda K, Katada T, Chiba S, Watanabe T, Ogawa S. Variegated RHOA mutations in adult T-cell leukemia/lymphoma. Blood, 127:596-604, 2016

10.Maeshima AM, Taniguchi H, Toyoda K, Yamauchi N, Makita S, Fukuhara S, Munakata W, Maruyama D, Kobayashi Y, Tobinai K. Clinicopathological features of histological transformation from extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue to diffuse large B-cell lymphoma: an analysis of 467 patients. Br J Haematol, 174:923-931, 2016

11.Ogura M, Tobinai K, Hatake K, Davies A, Crump M, Ananthakrishnan R, Ishibashi T, Paccagnella ML, Boni J, Vandendries E, MacDonald D. Phase I Study of Inotuzumab Ozogamicin Combined with R-CVP for Relapsed/Refractory CD22+ B-cell Non-Hodgkin Lymphoma. Clin Cancer Res, 22:4807-4816, 2016

12.Ogawa Y, Ogura M, Tobinai K, Ando K, Suzuki T, Watanabe T, Ohmachi K, Uchida T, Hanson ME, Tanaka Y, Koh Y, Shimamoto T, Hotta T. A phase I study of vorinostat combined with bortezomib in Japanese patients with relapsed or refractory multiple myeloma. Int J Hematol, 103:25-33, 2016

13.Ishida T, Fujiwara H, Nosaka K, Taira N, Abe Y, Imaizumi Y, Moriuchi Y, Jo T, Ishizawa K, Tobinai K, Tsukasaki K, Ito S, Yoshimitsu M, Otsuka M, Ogura M, Midorikawa S, Ruiz W, Ohtsu T. Multicenter Phase II Study of Lenalidomide in Relapsed or Recurrent Adult T-Cell Leukemia/Lymphoma: ATLL-002. J Clin Oncol, 34:4086-4093, 2016

14.Makita S, Maruyama D, Maeshima AM, Taniguchi H, Miyamoto K, Kitahara H, Fukuhara S, Munakata W, Kobayashi Y, Itami J, Tobinai K. Clinical features and outcomes of 139 Japanese patients with Hodgkin lymphoma. Int J Hematol, 104:236-244, 2016

15.Makita S, Maeshima AM, Taniguchi H, Kitahara H, Fukuhara S, Munakata W, Suzuki T, Maruyama D, Kobayashi Y, Tobinai K. Classical Hodgkin lymphoma primary refractory to brentuximab vedotin, with transformation to CD30-positive diffuse large B-cell lymphoma. Int J Hematol, 104:396-399, 2016

16.Miyamoto K, Kobayashi Y, Maeshima AM, Taniguchi H, Nomoto J, Kitahara H, Fukuhara S, Munakata W, Maruyama D, Tobinai K. Clinicopathological prognostic factors of 24 patients with B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and Burkitt lymphoma. Int J Hematol, 103:693-702, 2016

17.Crump M, Leppa S, Fayad L, Lee JJ, Di Rocco A, Ogura M, Hagberg H, Schnell F, Rifkin R, Mackensen A, Offner F, Pinter-Brown L, Smith S, Tobinai K, Yeh S-P, Hsi ED, Nguyen T, Shi P, Hahka-Kemppinen M, Thornton D, Lin B, Kahl B, Schmitz N, Savage KJ, Habermann T. Randomized, Double-Blind, Phase III Trial of Enzastaurin Versus Placebo in Patients Achieving Remission After First-Line Therapy for High-Risk Diffuse Large B-Cell Lymphoma. J Clin Oncol, 34:2484-2492, 2016

18.Iida S, Tobinai K, Taniwaki M, Shumiya Y, Nakamura T, Chou T. Phase I dose escalation study of high dose carfilzomib monotherapy for Japanese patients with relapsed or refractory multiple myeloma. Int J Hematol, 104:596-604, 2016

19.Igarashi T, Ogura M, Itoh K, Taniwaki M, Ando K, Kuroda Y, Yamamoto K, Uike N, Tomita A, Nagai H, Kurosawa M, Mori S, Nawano S, Terauchi T, Ohashi Y, Tobinai K. Japanese phase II study of rituximab maintenance for untreated indolent B-cell non-Hodgkin lymphoma with high tumor burden. Int J Hematol, 104:700-708, 2016

20.Iida S, Ogiya D, Abe Y, Taniwaki M, Asou H, Maeda K, Uenaka K, Nagaoka S, Ishiki T, Conti I, Tobinai K. Dose-escalation study of tabalumab with bortezomib and dexamethasone in Japanese patients with multiple myeloma. Cancer Sci, 107:1281-1289, 2016

21.Ohmoto A, Fuji S, Miyagi-Maeshima A, Tajima K, Tanaka T, Ito R, Inoue Y, Okinaka K, Kurosawa S, Inamoto Y, Yamashita T, Taniguchi H, Makita S, Kitahara H, Munakata W, Suzuki T, Maruyama D, Kobayashi Y, Tanosaki R, Tobinai K, Fukuda T, Kim SW. Prognostic factors in patients with relapsed or refractory diffuse large B-cell lymphoma who underwent autologous stem-cell transplantation. J Hematopoietic Cell Transplantation, 5:93-101, 2016

22.Yuda S, Maruyama D, Maeshima AM, Makita S, Kitahara H, Miyamoto K, Fukuhara S, Munakata W, Suzuki T, Kobayashi Y, Tajima K, Taniguchi H, Tobinai K. Influence of the watch and wait strategy on clinical outcomes of patients with follicular lymphoma in the rituximab era. Ann Hematol, 95:2017-2022, 2016

23.Kawajiri A, Maruyama D, Maeshima AM, Nomoto J, Makita S, Kitahara H, Miyamoto KI, Fukuhara S, Suzuki T, Munakata W, Tajima K, Itami J, Taniguchi H, Kobayashi Y, Tobinai K. Impact of the double expression of MYC and BCL2 on outcomes of localized primary gastric diffuse large B-cell lymphoma patients in the rituximab era. Blood Cancer J, 6:e477, 2016

24.Munakata W, Tobinai K. The discovery and the development of bendamustine for the treatment of non-Hodgkin lymphoma. Expert Opin Drug Discov, 11:1123-1130, 2016

25.Maruyama D, Nagai H, Fukuhara N, Kitano T, Ishikawa T, Shibayama H, Choi I, Hatake K, Uchida T, Nishikori M, Kinoshita T, Matsuno Y, Nishikawa T, Takahara S, Tobinai K. Efficacy and safety of ibrutinib in Japanese patients with relapsed or refractory mantle cell lymphoma. Cancer Sci, 107:1785-1790, 2016

26.Tada K, Maeshima AM, Hiraoka N, Yamauchi N, Maruyama D, Kim S-W, Watanabe T, Katayama N, Heike Y, Tobinai K, Kobayashi Y. Prognostic significance of HLA class I and II expression in patients with diffuse large B cell lymphoma treated with standard chemoimmunotherapy. Cancer Immunol Immunother, 65:1213-1222, 2016

27.Matsushita H, Maruyama D. Bone marrow involvement of primary cutaneous gamma/delta T-cell lymphoma. Blood, 128:2274, 2016

28.Yanada M, Kanda J, Ohtake S, Fukuda T, Sakamaki H, Miyamura K, Miyawaki S, Uchida N, Maeda T, Nagamura-Inoue T, Asou N, Morishima Y, Atsuta Y, Miyazaki Y, Kimura F, Kobayashi Y, Takami A, Naoe T, Kanda Y. Unrelated bone marrow transplantation or immediate umbilical cord blood transplantation for patients with acute myeloid leukemia in first complete remission. Eur J Haematol, 97:278-287, 2016