Annual Report 2017

Koji Izutsu, Dai Maruyama, Tatsuya Suzuki, Wataru Munakata, Suguru Fukuhara, Shinichi Makita, Tomotaka Suzuki, Sayako Yuda, Yuta Ito, Shunsuke Hatta

Introduction

 The Department of Hematology cooperates with the Department of Hematopoietic Stem Cell Transplantation (HSCT), and 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 (ATLL) (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 diseases we treat are leukemia, myelodysplastic syndrome, malignant lymphoma, and multiple myeloma (Table 1). These diseases in a certain status require hematopoietic stem cell transplantation (HSCT), therefore, our department cooperates with the Department of HSCT, and HSCTs are provided by the Department of HSCT. 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 hemato-

oncologists, pathologists, and oncologists of other areas 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 examinations, 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

 Our department is devoted to activities of the leading clinical study groups on hematological malignancies, which are the Japan Clinical Oncology Group, Lymphoma Study Group (JCOG-LSG) and the Japan Adult Leukemia Study Group (JALSG).

 Recently, we stated comprehensive target gene sequences, using the Next Generation Sequencer for hematological malignancies. We have constructed a tumor sample banking system,and the samples' DNA and RNAs are extracted and reserved for future use.

 This year, we authored or coauthored 44 articles related to hematological malignancies.

Clinical trials

 In 2017, we conducted 64 new-agent studies, including international ones. A substantial number of new agents against hematological malignancies in Japan have been evaluated in our department.

 We are conducting JCOG1305 trials for

newly-diagnosed patients with advanced stage of classic Hodgkin lymphoma,and JCOG1411 for newly-diagnosed patients with advanced stage of follicular lymphoma for JCOG-LSG, and JALSG N-STOP and D-STOP trials for patients with chronic myeloid leukemia.

Education

 We trained six chief residents and eight hematology residents following our residency program. We also trained many 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. More involvement in international studies is necessary, and more cooperative studies with other departments are awaited. Under a new department head's initiative, our department is further flourishing.

List of papers published in January 2017 - March 2018

Journal

 1. Ishitsuka K, Yurimoto S, Kawamura K, Tsuji Y, Iwabuchi M, Takahashi T, Tobinai K. Safety and efficacy of mogamulizumab in patients with adult T-cell leukemia-lymphoma in Japan: interim results of postmarketing all-case surveillance. Int J Hematol, 106:522-532, 2017

 2. Takeuchi J, Kusumoto S, Akiyama H, Kanda Y, Izutsu K. JSH guideline for tumors of hematopoietic and lymphoid tissues-leukemia: 3. Acute lymphoblastic leukemia/lymphoblastic lymphoma (ALL/LBL). Int J Hematol, 106:732-747, 2017

 3. 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, 7:e620, 2017

 4. Makita S, Tobinai K. Mogamulizumab for the treatment of T-cell lymphoma. Expert Opin Biol Ther, 17:1145-1153, 2017

 5. Maruyama D, Hatake K, Kinoshita T, Fukuhara N, Choi I, Taniwaki M, Ando K, Terui Y, Higuchi Y, Onishi Y, Abe Y, Kobayashi T, Shirasugi Y, Tobinai K. Multicenter phase II study of nivolumab in Japanese patients with relapsed or refractory classical Hodgkin lymphoma. Cancer Sci, 108:1007-1012, 2017

 6. Maruyama D, Tobinai K, Ogura M, Uchida T, Hatake K, Taniwaki M, Ando K, Tsukasaki K, Ishida T, Kobayashi N, Ishizawa K, Tatsumi Y, Kato K, Kiguchi T, Ikezoe T, Laille E, Ro T, Tamakoshi H, Sakurai S, Ohtsu T. Romidepsin in Japanese patients with relapsed or refractory peripheral T-cell lymphoma: a phase I/II and pharmacokinetics study. Int J Hematol, 106:655-665, 2017

 7. Makita S, Yoshimura K, Tobinai K. Clinical development of anti-CD19 chimeric antigen receptor T-cell therapy for B-cell non-Hodgkin lymphoma. Cancer Sci, 108:1109-1118, 2017

 8. Kobayashi Y, Sakura T, Miyawaki S, Toga K, Sogo S, Heike Y. A new peptide vaccine OCV-501: in vitro pharmacology and phase 1 study in patients with acute myeloid leukemia. Cancer Immunol Immunother, 66:851-863, 2017

 9. Makita S, Tobinai K. Clinical Features and Current Optimal Management of Natural Killer/T-Cell Lymphoma. Hematol Oncol Clin North Am, 31:239-253, 2017

10. Fuji S, Yamaguchi T, Inoue Y, Utsunomiya A, Moriuchi Y, Uchimaru K, Owatari S, Miyagi T, Taguchi J, Choi I, Otsuka E, Nakachi S, Yamamoto H, Kurosawa S, Tobinai K, Fukuda T. Development of a modified prognostic index for patients with aggressive adult T-cell leukemia-lymphoma aged 70 years or younger: possible risk-adapted management strategies including allogeneic transplantation. Haematologica, 102:1258-1265, 2017

11. Makita S, Tobinai K. Rituximab biosimilars: introduction into clinical practice. The Lancet. Haematology, 4:e342-e343, 2017

12. Makita S, Kurihara H, Tobinai K. Intravenacaval invasion of classical Hodgkin lymphoma detected with 18F-fluorodeoxyglucose (18F-FDG) PET-MRI. Lancet Oncol, 18:e233, 2017

13. Younes A, Hilden P, Coiffier B, Hagenbeek A, Salles G, Wilson W, Seymour JF, Kelly K, Gribben J, Pfreunschuh M, Morschhauser F, Schoder H, Zelenetz AD, Rademaker J, Advani R, Valente N, Fortpied C, Witzig TE, Sehn LH, Engert A, Fisher RI, Zinzani PL, Federico M, Hutchings M, Bollard C, Trneny M, Elsayed YA, Tobinai K, Abramson JS, Fowler N, Goy A, Smith M, Ansell S, Kuruvilla J, Dreyling M, Thieblemont C, Little RF, Aurer I, Van Oers MHJ, Takeshita K, Gopal A, Rule S, de Vos S, Kloos I, Kaminski MS, Meignan M, Schwartz LH, Leonard JP, Schuster SJ, Seshan VE. International Working Group consensus response evaluation criteria in lymphoma (RECIL 2017). Ann Oncol, 28:1436-1447, 2017

14. 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. Erratum to: Japanese phase II study of rituximab maintenance for untreated indolent B-cell non-Hodgkin lymphoma with high tumor burden. Int J Hematol, 105:109-110, 2017

15. Ogura M, Ishizawa K, Maruyama D, Uike N, Ando K, Izutsu K, Terui Y, Imaizumi Y, Tsukasaki K, Suzuki K, Izumi T, Usuki K, Kinoshita T, Taniwaki M, Uoshima N, Suzumiya J, Kurosawa M, Nagai H, Uchida T, Fukuhara N, Choi I, Ohmachi K, Yamamoto G, Tobinai K. Bendamustine plus rituximab for previously untreated patients with indolent B-cell non-Hodgkin lymphoma or mantle cell lymphoma: a multicenter Phase II clinical trial in Japan. Int J Hematol, 105:470-477, 2017

16. Maruyama D, Nagai H, Maeda Y, Nakane T, Shimoyama T, Nakazato T, Sakai R, Ishikawa T, Izutsu K, Ueda R, Tobinai K. Phase I/II study of pralatrexate in Japanese patients with relapsed or refractory peripheral T-cell lymphoma. Cancer Sci, 108:2061-2068, 2017

17. Ishida T, Utsunomiya A, Jo T, Yamamoto K, Kato K, Yoshida S, Takemoto S, Suzushima H, Kobayashi Y, Imaizumi Y, Yoshimura K, Kawamura K, Takahashi T, Tobinai K, Ueda R. Mogamulizumab for relapsed adult T-cell leukemia-lymphoma: Updated follow-up analysis of phase I and II studies. Cancer Sci, 108:2022-2029, 2017

18. Tobinai K, Klein C, Oya N, Fingerle-Rowson G. A Review of Obinutuzumab (GA101), a Novel Type II Anti-CD20 Monoclonal Antibody, for the Treatment of Patients with B-Cell Malignancies. Adv Ther, 34:324-356, 2017

19. Makita S, Munakata W, Watabe D, Maeshima AM, Taniguchi H, Toyoda K, Yamauchi N, Fukuhara S, Maruyama D, Kobayashi Y, Tobinai K. Azacitidine-induced acute lung injury in a patient with therapy-related myelodysplastic syndrome. J Int Med Res, 45:886-893, 2017

20. Kharfan-Dabaja MA, Kumar A, Ayala E, Hamadani M, Reimer P, Gisselbrecht C, d'Amore F, Jantunen E, Ishida T, Bazarbachi A, Foss F, Advani R, Fenske TS, Lazarus HM, Friedberg JW, Aljurf M, Sokol L, Tobinai K, Tse E, Burns LJ, Chavez JC, Reddy NM, Suzuki R, Ahmed S, Nademanee A, Mohty M, Gopal AK, Fanale MA, Pro B, Moskowitz AJ, Sureda A, Perales MA, Carpenter PA, Savani BN. Clinical Practice Recommendations on Indication and Timing of Hematopoietic Cell Transplantation in Mature T Cell and NK/T Cell Lymphomas: An International Collaborative Effort on Behalf of the Guidelines Committee of the American Society for Blood and Marrow Transplantation. Biol Blood Marrow Transplant, 23:1826-1838, 2017

21. Younes A, Ansell S, Fowler N, Wilson W, de Vos S, Seymour J, Advani R, Forero A, Morschhauser F, Kersten MJ, Tobinai K, Zinzani PL, Zucca E, Abramson J, Vose J. The landscape of new drugs in lymphoma. Nat Rev Clin Oncol, 14:335-346, 2017

22. Kitahara H, Maruyama D, Maeshima AM, Makita S, Miyamoto K, Fukuhara S, Munakata W, Suzuki T, Kobayashi Y, Tajima K, Terauchi T, Kurihara H, Taniguchi H, Komatsu N, Tobinai K. Prognosis of patients with peripheral T cell lymphoma who achieve complete response after CHOP/CHOP-like chemotherapy without autologous stem cell transplantation as an initial treatment. Ann Hematol, 96:411-420, 2017

23. Yamaguchi M, Suzuki R, Oguchi M, Asano N, Amaki J, Akiba T, Maeda T, Itasaka S, Kubota N, Saito Y, Kobayashi Y, Itami J, Ueda K, Miyazaki K, Ii N, Tomita N, Sekiguchi N, Takizawa J, Saito B, Murayama T, Ando T, Wada H, Hyo R, Ejima Y, Hasegawa M, Katayama N. 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, 35:32-39, 2017

24. Munakata W, Ohashi K, Yamauchi N, Tobinai K. Fulminant type I diabetes mellitus associated with nivolumab in a patient with relapsed classical Hodgkin lymphoma. Int J Hematol, 105:383-386, 2017

25. Takeuchi J, Kusumoto S, Akiyama H, Kanda Y, Izutsu K. JSH guideline for tumors of hematopoietic and lymphoid tissues-leukemia: 3. Acute lymphoblastic leukemia/lymphoblastic lymphoma (ALL/LBL). Int J Hematol, 106:732-747, 2017

26. Nosaka K, Iwanaga M, Imaizumi Y, Ishitsuka K, Ishizawa K, Ishida Y, Amano M, Ishida T, Uike N, Utsunomiya A, Ohshima K, Kawai K, Tanaka J, Tokura Y, Tobinai K, Watanabe T, Uchimaru K, Tsukasaki K. Epidemiological and clinical features of adult T-cell leukemia-lymphoma in Japan, 2010-2011: A nationwide survey. Cancer Sci, 108:2478-2486, 2017

27. Maeshima AM, Taniguchi H, Suzuki T, Yuda S, Toyoda K, Yamauchi N, Makita S, Fukuhara S, Munakata W, Maruyama D, Kobayashi Y, Tobinai K. Distribution of malignant lymphomas in the anterior mediastinum: a single-institution study of 76 cases in Japan, 1997-2016. Int J Hematol, 106:675-680, 2017

28. Maeshima AM, Taniguchi H, Suzuki T, Yuda S, Toyoda K, Yamauchi N, Makita S, Fukuhara S, Munakata W, Maruyama D, Kobayashi Y, Saito Y, Tobinai K. Comparison of clinicopathologic characteristics of gastric follicular lymphomas and duodenal follicular lymphomas. Hum Pathol, 65:201-208, 2017

29. Katanoda K, Shibata A, Matsuda T, Hori M, Nakata K, Narita Y, Ogawa C, Munakata W, Kawai A, Nishimoto H. Childhood, adolescent and young adult cancer incidence in Japan in 2009-2011. Jpn J Clin Oncol, 47:762-771, 2017

30. Minami Y, Minami H, Miyamoto T, Yoshimoto G, Kobayashi Y, Munakata W, Onishi Y, Kobayashi M, Ikuta M, Chan G, Woolfson A, Ono C, Shaik MN, Fujii Y, Zheng X, Naoe T. Phase I study of glasdegib (PF-04449913), an oral smoothened inhibitor, in Japanese patients with select hematologic malignancies. Cancer Sci, 108:1628-1633, 2017

31. Makita S, Tobinai K. Disease-oriented treatment of T-cell lymphoma. Hematol Oncol, 35 Suppl 1:54-59, 2017

32. Hermine O, Ramos JC, Tobinai K. A Review of New Findings in Adult T-cell Leukemia-Lymphoma: A Focus on Current and Emerging Treatment Strategies. Adv Ther, 35:135-152, 2018

33. Fukuhara S, Nomoto J, Kim SW, Taniguchi H, Miyagi Maeshima A, Tobinai K, Kobayashi Y. Partial deletion of the ALK gene in ALK-positive anaplastic large cell lymphoma. Hematol Oncol, 36:150-158, 2018

34. Kobayashi Y, Munakata W, Ogura M, Uchida T, Taniwaki M, Kobayashi T, Shimada F, Yonemura M, Matsuoka F, Tajima T, Yakushijin K, Minami H. Phase I study of panobinostat and 5-azacitidine in Japanese patients with myelodysplastic syndrome or chronic myelomonocytic leukemia. Int J Hematol, 107:83-91, 2018

35. Sakura T, Hayakawa F, Sugiura I, Murayama T, Imai K, Usui N, Fujisawa S, Yamauchi T, Yujiri T, Kakihana K, Ito Y, Kanamori H, Ueda Y, Miyata Y, Kurokawa M, Asou N, Ohnishi K, Ohtake S, Kobayashi Y, Matsuo K, Kiyoi H, Miyazaki Y, Naoe T. High-dose methotrexate therapy significantly improved survival of adult acute lymphoblastic leukemia: a phase III study by JALSG. Leukemia, 32:626-632, 2018

36. Takahashi N, Tauchi T, Kitamura K, Miyamura K, Saburi Y, Hatta Y, Miyata Y, Kobayashi S, Usuki K, Matsumura I, Minami Y, Usui N, Fukuda T, Takada S, Ishikawa M, Fujimaki K, Gomyo H, Sasaki O, Ohishi K, Miyake T, Imai K, Suzushima H, Mitsui H, Togitani K, Kiguchi T, Atsuta Y, Ohtake S, Ohnishi K, Kobayashi Y, Kiyoi H, Miyazaki Y, Naoe T. Deeper molecular response is a predictive factor for treatment-free remission after imatinib discontinuation in patients with chronic phase chronic myeloid leukemia: the JALSG-STIM213 study. Int J Hematol, 107:185-193, 2018

37. Kawashima I, Inamoto Y, Maeshima AM, Nomoto J, Tajima K, Honda T, Shichijo T, Kawajiri A, Takemura T, Onishi A, Ito A, Tanaka T, Fuji S, Kurosawa S, Kim SW, Maruyama D, Tobinai K, Kobayashi Y, Fukuda T. Double-Expressor Lymphoma Is Associated with Poor Outcomes after Allogeneic Hematopoietic Cell Transplantation. Biol Blood Marrow Transplant, 24:294-300, 2018

38. Kwong YL, Kim SJ, Tse E, Oh SY, Kwak JY, Eom HS, Do YR, Mun YC, Lee SR, Shin HJ, Suh C, Chuang SS, Lee YS, Lim ST, Izutsu K, Suzuki R, Relander T, d'Amore F, Schmitz N, Jaccard A, Kim WS. Sequential chemotherapy/radiotherapy was comparable with concurrent chemoradiotherapy for stage I/II NK/T-cell lymphoma. Ann Oncol, 29:256-263, 2018

39. Sudo K, Kato K, Kuwabara H, Sasaki Y, Takahashi N, Shoji H, Iwasa S, Honma Y, Okita NT, Takashima A, Hamaguchi T, Yamada Y, Ito Y, Itami J, Fukuda T, Tobinai K, Boku N. Patterns of Relapse after Definitive Chemoradiotherapy in Stage II/III (Non-T4) Esophageal Squamous Cell Carcinoma. Oncology, 94:47-54, 2018

40. Kataoka K, Iwanaga M, Yasunaga JI, Nagata Y, Kitanaka A, Kameda T, Yoshimitsu M, Shiraishi Y, Sato-Otsubo A, Sanada M, Chiba K, Tanaka H, Ochi Y, Aoki K, Suzuki H, Shiozawa Y, Yoshizato T, Sato Y, Yoshida K, Nosaka K, Hishizawa M, Itonaga H, Imaizumi Y, Munakata W, Shide K, Kubuki Y, Hidaka T, Nakamaki T, Ishiyama K, Miyawaki S, Ishii R, Nureki O, Tobinai K, Miyazaki Y, Takaori-Kondo A, Shibata T, Miyano S, Ishitsuka K, Utsunomiya A, Shimoda K, Matsuoka M, Watanabe T, Ogawa S. Prognostic relevance of integrated genetic profiling in adult T-cell leukemia/lymphoma. Blood, 131:215-225, 2018

41. Witzig TE, Tobinai K, Rigacci L, Ikeda T, Vanazzi A, Hino M, Shi Y, Mayer J, Costa LJ, Bermudez Silva CD, Zhu J, Belada D, Bouabdallah K, Kattan JG, Kuruvilla J, Kim WS, Larouche JF, Ogura M, Ozcan M, Fayad L, Wu C, Fan J, Louveau AL, Voi M, Cavalli F. Adjuvant everolimus in high-risk diffuse large B-cell lymphoma: final results from the PILLAR-2 randomized phase III trial. Ann Oncol, 29:707-714, 2018

42. Higashiyama RI, Makita S, Maeshima AM, Maruyama D. Atypical radiological presentation of pulmonary invasion of diffuse large B-cell lymphoma mimicking Pneumocystis jiroveci pneumonia. Jpn J Clin Oncol, 48:298-299, 2018

43. Ohmachi K, Ando K, Ogura M, Uchida T, Tobinai K, Maruyama D, Namiki M, Nakanishi T. E7777 in Japanese patients with relapsed/refractory peripheral and cutaneous T-cell lymphoma: A phase I study. Cancer Sci, 109:794-802, 2018

44. Tanaka Y, Maeshima AM, Nomoto J, Makita S, Fukuhara S, Munakata W, Maruyama D, Tobinai K, Kobayashi Y. Expression pattern of PD-L1 and PD-L2 in classical Hodgkin lymphoma, primary mediastinal large B-cell lymphoma, and gray zone lymphoma. Eur J Haematol, 100:511-517, 2018