Hematology

Introduction
The Hematology Division is a part of the Division of Oncology and Hematology. Accordingly, all six staff physicians and two residents are involved in the clinical and research activities of chemotherapy for patients with both hematological and non-hematological tumors in this division. The same physicians also perform stem cell harvest by apheresis, cell processing and high dose chemotherapy with autologous stem cell transplantation. The number of patients with hematological malignancies has been increasing annually. In particular, more than 80 patients with malignant lymphoma are seen in this division each year.

Routine Activities 
We manage various kinds of hematological malignancies including non-Hodgkin's lymphoma, Hodgkin's lymphoma, multiple myeloma, acute leukemia, chronic myeloid leukemia, myelodysplastic syndrome and others. We also manage most patients treated with aggressive chemotherapy in the 8F ward in which we have 8 laminar air flow rooms. Case conference on these patients is practiced everyday with nurses. High-dose chemotherapy with autologous hematopoietic stem cell transplantation is considered the standard treatment for relapsed non-Hodgkin's lymphoma. Therefore, the procedure of peripheral blood stem cell harvest and transplantation is increasing. Our clinical practice consists of not only the treatment of patients but also consultation concerning hematological abnormalities. There is a weekly case conference on Tuesday afternoon in the Division of Oncology/Hematology and a monthly joint conference on malignant lymphoma with pathologists. There are also morning journal clubs on Monday, Thursday and Friday in the Division of Oncology/Hematology.

Research Activities
The following clinical trials were conducted in this year.
Phase I trial
1) ZD 6474
2) HMR1275
3) BAY 43-9006
4) SHL 749 (Zevalin)
Phase I/II trials
1) Phase I/II study of CPT-11 and CDDP for relapsed non-Hodgkin's lymphoma
2) Pharmacological study of doxorubicin in 75% CHOP for elderly patients with aggressive non-Hodgkin's lymphoma
3) Phase I/II study of etoposide and cytarabine for relapsed large B-cell and peripheral T-cell lymphoma
Phase II trials
1) IDEC-C2B8 alone for relapsed aggressive non-Hodgkin's lymphoma
2) KW 2307 (Naverbine) for recurrent multiple myeloma
3) JCOG-9801 for adult T-cell leukemia and lymphoma
4) JCOG 0005-DI for multiple myeloma (VAD followed by high dose chemotherapy with autologous hematopoietic stem cell transplantation)
5) Erythropoietin for anemia accompanied with non- Hodgkin's lymphoma
Phase III trials
1) JCOG-9809, randomized study of standard CHOP and biweekly CHOP, for non-Hodgkin's lymphoma
2) JALSG (Japan Adult Leukemia Study Group) AML 201 for acute myeloid leukemia
3) JCOG-0112, randomized study of prednisolone and interferon, for responded multiple myeloma
4) JCOG-0203-MF, randomized study of Rituximab-CHOP and Rituximab-biweekly CHOP, for low grade non-Hodgkin's lymphoma
Others
1) Pharmacological study of cyclophosphamide
2) PET study in non-Hodgkin's lymphoma


New Developments in 2002
A mouse-human chimeric anti-CD20 monoclonal antibody (rituximab) has demonstrated high response rates with only mild toxic effects in B-cell lymphoma. National Cancer Center played an important role in the development of rituximab in Japan. In this year, phase II study of rituximab monotherapy with 8 weekly infusions against aggressive non-Hodgkin's lymphoma (B-NHL) was completed. A total of 68 patients were enrolled into the trial. The overall response rate was 35% (95% confidence interval [CI], 24% to 48%) in patients enrolled. Similar response rate (37%; 95% CI, 24% to 51%) was observed in eligible 57 patients. The response rate was comparable to the previous European study. By multivariate analysis, high serum LDH level and primary refractoriness to prior chemotherapy (versus relapsed) were significant in predicting poor response. Pharmacokinetics of rituximab showed that trough levels and AUCs in responded patients were significantly higher than those in non-responders. And interestingly, serum levels of rituximab in patients with aggressive B-NHL were significantly higher than those in patients with indolent B-NHL by comparison with data up to 4 infusions for both groups. Median progression-free survival after rituximab treatment was 52 days (95% CI, 33 -111 days) and median time to progression in responders was 245 days (95% CI, 176 -435 days).
Generally, lymphoma cells are inherently sensitive to radiotherapy. And, even in treatment with rituximab, tumor cells distant from the bound antibody can be killed by ionizing radiation from beta-emitting isotopes in bulky or poorly vascularized tumors. Accordingly, radioimmunotherapy is a potentially effective new therapy for B-NHL. A phase I study of Yttrium-90-labeled anti-CD20 antibody (Zevalin) was started. At the present time, trace-labelled dose of 0.3mCi/kg of Yttrium-90 is being evaluated. Most non-hematological adverse events observed were related to rituximab infusions. Adverse events were primarily hematological and reversible. Favorable response was also observed.

K. ITO

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