Hematology Division

Introduction
The Hematology Division is allied with the Hematopoietic Stem Cell Transplantation (HSCT) Division, and the two divisions are fully integrated. In the past, our division introduced to the world a retrovirusassociated, novel lymphoid malignancy, adult T-cell leukemia-lymphoma (ATL), and a new disease entity called immunoblastic lymphadenopathy (IBL)-like T-cell lymphoma. The division is one of the leading hematologyoncology centers in the world in the number of patients treated and in its research activity, especially for malignant lymphoma.

Routine Activities
The number of newly diagnosed cases of hematological malignancies in our division has markedly increased annually from 86 in 1997 to 140 in 1998, 199 in 1999, 267 in 2000 and 295 in 2001. The number of patients who visit our clinic to obtain a second opinion is also increasing. We hold a weekly case conference where a summary of each hospitalized- or out-patient is presented. A weekly cytology conference is held for education of young doctors. Newly diagnosed lymphoma cases are presented at the weekly lymphoma conference, where medical oncologists, pathologists, radiologists, and radiation oncologists discuss diagnoses and treatment plans. We also participate in weekly HSCT conferences, which deal with all HSCT cases.
Our daily duties include maintaining one hematology clinic and performing bone marrow puncture or biopsy, microscopic examination, flow cytometric analysis, and molecular analysis. Three staff physicians, one chief resident, two residents, and one rotating fellow share these activities.

Research Activities
We have introduced a new classification system (World Health Organization Classification) into our routine practices on lymphoma diagnoses. Molecular diagnosis is routinely performed as a laboratory test using Southern blot hybridization, polymerase chain reaction (PCR), and fluorescence in situ hybridization (FISH). We established a novel dual-color FISH for the detection of t(11;18), which specifically identifies a subset of mucosa-associated lymphoid tissue (MALT)-lymphoma.
In 2001 we published 6 original articles. Among the 6 original articles published and 3 in press, the following are important: Japanese pivotal phase II study of rituximab, a chimeric anti-CD20 monoclonal antibody, in Annals of Oncology; detection of t(11;18) MALT-type lymphoma in Diagnostic Molecular Pathology; and a JCOG study 9303 for ATL in British Journal of Hematology.

Clinical Trials
Current clinical trials include 5 new agent studies (1 molecular targeting therapy, 2 monoclonal antibody studies, 1 interferon study, and 1 navelbine study), 3 phase II and 3 phase III studies of combination chemotherapies. Of these, the molecular targeting therapy and the monoclonal antibody studies are unique. We participated in a phase I/II study of STI571, a BCR-ABL-specific tyrosine kinase inhibitor, for chronic myelogenous leukemia in accelerated or blastic phase. All 10 patients enrolled from our division showed hematological responses, including 5 complete cytogenetic responses, which were remarkable results. STI571 was approved by the Ministry of Health, Labor and Welfare (MHLW) in December 2001. We expect that the prognosis of CML patients will be improved dramatically.
The results of the phase I and II studies of rituximab against relapsed B-lymphoma that we have conducted were submitted to the MHLW, and rituximab was approved in September 2001. We completed the patient enrollment into two kinds of phase II studies: a randomized phase II study of CHOP (cyclophosphamide, doxorubicin, vincristine and prednisone) plus rituximab to compare concurrent and sequential administrations in untreated indolent B-lymphoma and a single agent phase II study against relapsed aggressive B-lymphoma and. In the latter phase II study we obtained 38% of overall response rate (26/68). We are going to submit the data to the MHLW as soon as possible to obtain a license for aggressive B-lymphoma. We believe that rituximab will improve the prognosis of B-lymphoma patients. Now we are ready to initiate a new phase II/III study comparing CHOP plus rituximab and biweekly CHOP plus rituximab, expecting the synergistic effect of rituximab and granulocyte colony-stimulating factor (G-CSF). In addition, we conducted a phase I/II study of CMA-676 (a calicheamicin-conjugated humanized anti-CD33 monoclonal antibody) against acute myelocytic leukemia (AML). Of the 20 patients with relapsed or refractory AML, 7 (35%) achieved complete responses.
We are conducting a randomized phase III trial comparing G-CSF-supported biweekly CHOP versus standard CHOP therapy against advanced aggressive lymphoma (JCOG 9809). In the treatment of ATL, we are conducting a randomized phase III trial (JCOG 9801) to compare G-CSF-supported multi-agent chemotherapy versus biweekly CHOP therapy. In the treatment of multiple myeloma, we started a feasibility study of HDC with autologous HSCT, and we are going to initiate a phase III trial to evaluate the efficacy of maintenance therapy with interferon-alfa and prednisone.

K. TOBINAI

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