Hematology

Introduction
The treatment for hematological malignancies is one of activities in the Division of Oncology and Hematology in NCCHE. 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 malignancies in this division. In other words, 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 withhematological 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 haematological malignancies including non-Hodgkinis lymphoma,Hodgkinis lymphoma, multiple myeloma, acute leukemia, chronic myeloid leukemia, myelodysplasticsyndrome and others. We also manage most patients treated with aggressive chemotherapy in the 8F ward inwhich we have 8 laminar air flow rooms. High-dose chemotherapy with autologous hematopoietic stem cell transplantation is considered as a standard treatment for relapsed non-Hodgkinis 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 hemato-logical 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. Also, we have morning journal clubs on Monday, Thursday and Friday in the Division of Oncology/Hematology.

Research Activities
The following clinical trials were conducted this year:
Phase I trial
1) ZD 6474
2) SHT 58
3) HMR1275
4) CGP 42446 for patients ccompanying hyper-calcemia
5) Weekly RP 56976
Phase I/II trials
1) Phase I/II study of CPT-11 and CDDP for relapsed non-Hodgkinis lymphoma
2) Feasibilitystudy of 75% CHOP for elderly patients with aggressive non-Hodgkinis lymphoma
3) Phase I/II study of A643 for low-grade non-Hodgkinis lymphoma
Phase II trials
1) Combination of IDEC-C2B8 (monoclonal antibody against CD20) and CHOP for untreated low grade non-Hodgkinis lymphoma
2) IDEC-C2B8 alone for relapsed aggressive non-Hodgkinis lymphoma
3) KW 2307 for recurrent multiple myeloma
4) JCOG-LSG 16 for lymphoblastic lymphoma or acute lymphoblastic leukemia
5) JCOG-LSG 22 for Hodgkinis lymphoma 6) JCOG-9801 for adult T-cell leukemia and lymphoma
7) JCOG 0005-DI for multiple myeloma (VAD followed by high dose chemotherapy withautologous hematopoietic stem cell transplantation).
Phase III trials
1) JCOG-9809, randomized study of standard CHOP and biweekly CHOP, for non-Hodgkinis lymphoma
2) JALSG (Japan Adult Leukemia Study Group) AML 97 for acute myeloid leukemia
3) JALSG APL 97 for acute promyelocytic leukemia

New Developments
In the US, a mouse-human chimerical anti-CD20 monoclonal antibody (Rituximab) has demonstrated highresponse rates with only mild toxic effects in relapsed B-cell lymphoma. National Cancer Center played an important role in the development of Rituximab in Japan. At the first step, patients with relapsed CD20+ low grade B-cell lymphoma received intravenous infusions of Rituximab once a week for four weeks. A total of 12 patients were enrolled in the phase I trial. Commonly observed adverse drug reactions were mild nonhematologic toxicities during the infusion. Two complete responses and five partial responses were observed. A pharmacokinetic analysis showed that the elimination half-life (T1/2) of Rituximab was 445 +/- 361 hours, and hat the serum antibody levels increased in parallel with the course of infusion and in most patients was still measurable at three months. Thereafter, phase II studies of Rituximab combined with CHOP for low-grade lymphoma and used alone for relapsed aggressive lymphoma were conducted.
The re-treatment with rituximab in those with indolent B-cell lymphoma who responded to rituximab inthe previous phase I/II study was also performed. Thirteen patients with relapsed B cell NHL, each of whom wasconfirmed to have Revised European-American Lymphoma Classification type II, 1-6 histology (indolent BNHL)at being enrolled in this re-treatment study. All were re-treated with rituximab at 375 mg/m2 weekly for 4 consecutive weeks. Rituximab re-treatment was well tolerated with no grade 3/4 non-hematological toxicities,similar to that of the initial treatment. No patients developed detectable human anti-chimerical antibody. Partialresponses were observed in 5 of 13 patients (38%; 95% confidence interval [CI], 14% to 68%); 6 patientsshowed stable disease and 2 showed progressive disease. Overall survival rate was 93% at 19 months of medianfollow-up after rituximab re-treatment. Median progression-free survival (PFS) after the re-treatment was 5.1months (95% CI, 4.1 to 5.6 months), and the median PFS after the initial treatment was 8.2 months (95%CI, 5.9to 11.3 months). Although rituximab re-treatment induced prolonged depletion of normal peripheral blood Bcells in all patients, no significant decrease in serum immunoglobulin or complement level was observed. In conclusion, rituximab re-treatment was well tolerated, and it may produce a prolonged PFS in some patients withindolent B cell NHL who showed initial response to rituximab.

K. ITO

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