Pure red cell aplasia and myelofibrosis in B-cell neoplasm.

We describe an unusual case of B-cell neoplasm accompanied by pure red cell aplasia (PRCA) and myelofibrosis in a 67-year-old male presenting with severe anaemia. A few unclassified, myeloperoxidase-negative blastoid cells were seen on bone marrow aspiration, and erythroid cell hypoplasia and myelofibrosis on bone marrow biopsy. An autoimmune PRCA was suspected, as serum CH50, C3 and C4 levels were consistently low. Ciclosporin was effective in treating the anaemia, but anaemia returned when the drug was discontinued. Thirteen months later, the patient was admitted with pleural effusion and ascites that contained monoclonal CD19+ CD20+ immature blast cells with a complex karyotype, thought to be neoplastic B-cells. The unclassified blastoid cells seen earlier may therefore have been from the same origin. The patient deteriorated rapidly and died. Only one case of non-Hodgkin's lymphoma with PRCA and myelofibrosis has been reported previously. We discuss the possibility that dysregulated T-cells induced by neoplastic B-cells may have given rise to concomitant PRCA and myelofibrosis.

WT1 expression level and clinical factors in multiple myeloma.

Although Wilm's Tuomor gene (WT1) was first identified as a tumor suppressor gene for Wilm's tumor, WT1 overexpression has been detected in different malignant cell types including leukemia. Increased expression of WT1 in acute leukemia is potentially used as a marker of minimal residual disease. However, the significance of the gene for multiple myeloma is still not clear. To determine the clinical relevance of WT1 expression in multiple myeloma, we examined the association of clinical parameters and WT1 expression in bone marrow for 17 newly diagnosed multiple myeloma patients. WT1 was assessed by real-time quantitative polymerase chain reaction (RQ-PCR) and calculated standardized WT1 expression level per 100 plasma cells in the bone marrow specimen as "corrected WT1". The expression of standardized WT1 and corrected WT1 in myeloma was 59 to 1,600 copies/microg RNA and 0.05 to 406.3 copies/microg RNA/100 plasma cells, respectively, lower than in leukemia. WT1 transcripts increased when clinical factors worsen, including the stage, amount of M protein, Hb, platelet count, blood urea nitrogen (BUN), creatinine, serum alkaline phosphatase (ALP), calcium, beta2-microglobulin, thymidine kinase activity (TK), and C-reactive protein (CRP). In conclusion, the expression level of WT1 could be an additional marker to the standard parameters considered in risk assessment for multiple myeloma.

Huge IgD plasmacytoma in the abdomen presenting coagulation necrosis.

A 65-year-old Japanese woman was diagnosed in 1996 with a pathological fracture of the left femur caused by immunoglobulin D-type myeloma (IgD myeloma). She responded well to combination chemotherapy followed by irradiation. The patient experienced renal failure and became dependent on haemodialysis. In 1999, large plasmacytomas developed in the abdomen and left humerus. The abdominal tumour appeared to induce gastroduodenal ulcers and jejunal obstruction. We initiated irradiation therapy without chemotherapy to prevent further growth of the plasmacytoma, although treatment-resistant gastroduodenal ulcers developed. Continued blood loss from the gastroduodenal ulcers resulted in a deterioration in the patient's health, which prevented successful haemodialysis. An autopsy showed that the plasmacytoma had undergone coagulation necrosis. We conclude that the use of combination chemotherapy with topical irradiation was an acceptable treatment measure against IgD plasmacytoma; irradiation without chemotherapy was the most likely cause of the coagulation necrosis seen in the plasmacytoma at autopsy.

[Phenotypic classification of malignant lymphoma].

The phenotypic characters of the lymphoma cell are important in the diagnosis of this disease. We recently tested whether the flow cytometry with fresh biopsy sample might be useful in the diagnosis of the lymphoma. In our date, 1. a rise and fall of the surface immunoglobulin kappa/lambda ratio indicated the monoclonal proliferation of the B-cell, 2. the increased proportion of the CD5/CD23 double positive cells indicated B-cell chronic lymphocytic leukemia or small lymphocytic lymphoma, 3. the decreased proportion of the CD2 positive cells and the increased proportion of the CD19 positive cells indicated B-cell lymphoma. These findings suggest that the flow cytometry is of adjunctive importance in making a diagnosis of the lymphoma.

[Treatment of intermediate and high grade non-Hodgkin's lymphoma].

Since the study by SWOG in 1993, CHOP regimen has been the standard therapy for patients with advanced stage intermediate-grade or high-grade non-Hodgkin's lymphoma. Three-year estimated survival for all patients was about 50%. However, five-year disease free survival of the patients with high or high-intermediate risk by age-adjusted international prognostic index(IPI) is less than 30%. For the patients with low and low-intermediate IPI, high cure rate can be achieved by CHOP, or modified CHOP therapy. For the patients in high or high-intermediate risk groups, the CHOP regimen is not satisfactory. High-dose chemotherapy with haematopoietic stem cell rescue has been tried for those patients. We are conducting pilot study of high-dose chemotherapy with peripheral blood stem cell transplant(PBSCT) following induction with double CHOP regimen. Although the results are encouraging, confirmation with randomized prospective trials are necessary.

[Clinical outcomes in low grade follicular lymphoma].

Twenty-six patients with follicular small-cleaved lymphoma (FSCL) and 16 patients with follicular mixed lymphoma (FML) were treated at the Nichidai Itabashi Hospital between 1981 and 1995. The 5-year overall survival rate was 74.3% and 70.0% for the FSCL and FML patients, respectively. Of the patients with stage III-IV FSCL, 9 were assigned to a "watchful waiting" follow-up course and 13 were treated with a single alkylating agent or CHOP therapy. The 5-year failure-free survival rate was 66.7% and 33.0%, respectively. Of the patients with stage II-IV FML, 6 were treated with CHOP or MACOP-B protocol. The complete response rate for this group was only 33.3%, and none of the patients were in remission for more than 2 years. Histological transformation into diffuse aggressive lymphoma was observed in 7 patients, with the median time from diagnosis to transformation at 50 months. Three of those patients were successfully treated with intensive chemotherapy after transformation.

[Merocyanine 540-mediated photodynamic therapy inhibits P-glycoprotein (P-gp) activity in adriamycin-resistant K562 cells].

The photosensitizing dye merocyanine 540 (MC540) has been used in preclinical models and in a phase I clinical trial in the U.S.A. for the extracorporeal purging of autologous bone marrow grafts contaminated with leukemia or lymphoma. In this communication, we report MC540-mediated photodynamic therapy (PDT) was effective in purging leukemic cells expressing P-gp. When K562 and K562/ADM were exposed to MC540 (15 micrograms/ml) and white light (145.8 kJ/m2), the concentration of K562 and K 562/ADR was reduced by 1.8 and 3.0 log, respectively. Using flow cytometry and confocal laser scan microscopy, MC540 and calcein-AM were bound intracellularly and effluxed by P-gp in K562/ADM. In K562/ADM, calcein-AM efflux was inhibited by P-gp modulator, cyclosporin A (5 microM) and verapamil (15 micrograms/ml). In contrast, MC540 efflux was inhibited by cyclosporin A but not verapamil. Furthermore, MC540-mediated PDT inhibited efflux of calcein-AM and MC540, and induced the accumulation of dyes in K562/ADM. We conclude that MC540 is a substrate of P-gp and that MC540-mediated PDT is useful for purging MDR cells through inhibition of P-gp activity.

Antithymocyte globulin for a patient with systemic lupus erythematosus complicated by severe pancytopenia.

The clinical use of antithymocyte globulin is rarely reported in patients with rheumatic diseases. We describe the use of this agent in a patient with systemic lupus erythematosus who concomitantly developed severe pancytopenia. High-dose methylprednisolone therapy had been unsuccessful in controlling either the disease exacerbation or the pancytopenia. Antithymocyte globulin and cyclosporin A were therefore administered to achieve immunosuppression. The exacerbation of disease activity was gradually lessened, except for persistent thrombocytopenia and anaemia. Severe and persistent immunosuppression, however, led to a fatal brain abscess. The combined use of both antithymocyte globulin and cyclosporin A induced potent immunosuppression, and should be confined to selected patients with systemic lupus erythematosus, and administered under detailed monitoring.

Hepatitis B virus carriers in the treatment of malignant lymphoma: an epidemiological study in Japan.

BACKGROUND: Hepatitis B after the withdrawal of cytotoxic chemotherapy in hepatitis B virus (HBV) carriers is well known and may lead to fatal hepatic failure. We retrospectively analyzed the prevalence of HBV carriers, the incidence, and the risk factors of hepatitis B in the treatment of malignant lymphoma. PATIENTS AND METHODS: HBV carriers were defined as patients with positive HBs-antigen, either with normal or abnormal serum aminotransferase level at patient presentation. Questionnaires to the members of the Japan Lymphoma Treatment Study Group included general information, details about HBV carriers, and further information about hepatitis B. RESULTS: Among 1380 patients collected from eight institutions, 45 patients (3.26%) were determined to be HBV carriers, Hepatitis B developed in 17 of the HBV carrying patients (37.8%). Seven of those 17 (41.2%) died of hepatic failure. Hepatitis developed at a high rate in patients who were negative for HBe-antigen (50%), and who had received second- or third-generation chemotherapy (63.2%). CONCLUSION: We confirmed that hepatitis B developed with high frequency in HBV carriers with malignant lymphoma. Moreover, hepatitis often resulted in fatal hepatic failure. It is necessary to prevent the hepatitis B developing in HBV carriers when receiving intensive chemotherapy for malignant lymphoma.

Clinical analysis of malignant lymphomas of tonsils.

Data of 38 patients with primary tonsil lymphoma, treated during the past 14 years was analysed. All cases were non-Hodgkin lymphomas. There were 11 patients with Stage 1, 14 with Stage II, 8 with Stage III, and 4 with Stage IV tonsillar lymphomas. The applied chemotherapies were CHOP or MACOP-B regimen. The overall 5-year survival rate was 64.4%. Further analysis of the intermediate grade group showed that 5-year survival rates were 72.7%) for patients younger than 60 years old, in contrast to 35.0% for patients aged 60 or older (p 0.0049). Five-year survival rates were 100%) for Stage I, 32.4% for Stage II, 55.6% for Stage III, and 100%) for Stage IV patients (p = 0.0878). In patients with Stage II tonsillar lymphomas, 5-year survival rates were below 100% for CHOP regimen, 100% for MACOP-B regimen, 66.7% for radiation alone, and 0% for radiation followed by chemotherapy (p = 0.1966). In patients with Stage III tonsillar lymphomas, 5-year survival rates were below 100% for MACOP-B regimen, and 0% for initial radiation followed by chemotherapy (p = 0.2568). The factors influencing survival were age, stage, and treatment modality. For Stage I patients without bulky mass, radiation therapy is sufficient. For Stage II patients or Stage I patients with a bulky mass, CHOP regimen (followed by radiation) is the choice of treatment. For Stage III or IV patients,, MACOP-B regimen is promising.

[Daily oral low-dose etoposide therapy for aged patients with relapsed aggressive lymphoma].

Two patients with relapsed Non-Hodgkin's lymphoma (NHL) were treated with oral administration of etoposide. In these patients, long-term hematological remission was obtained. One patient was a 76-year-old man, who was successfully treated with CHOP for diffuse large cell NHL stage III B. One year after obtaining CR, he was admitted to our hospital for enlargement of lymph node. Rebiopsy of lymph node made a diagnosis of relapse from NHL. A new regimen of oral administration of etoposide treatment was employed. Hematological remission was obtained and continued for 3 years. Without interfering with his quality of life. The other patient was a 74-year-old man, who was treated with 6 cycles of CHOP for diffuse large cell NHL stage IV B. The patient attained complete remission following an additional 2 cycles of COMLA therapy. Eight years later, he was admitted for enlargement of lymph node. Rebiopsy of lymph node provided the basis for a diagnosis of relapse from NHL. Oral administration of etoposide treatment was started. Hematological remission was obtained and has been continued until now. These results show that oral administration of etoposide treatment is effective for some patients with recurrent NHL.

[Long term remission following relapsed CNS lymphoma].

A case of NHL which has been in long-term remission following vigorous treatment for CNS relapse with intrathecal administration of Ara-C and focal irradiation to the brain is presented. The patient was a 61-year-old man, who was successfully treated with CHOP followed by MACOP-B for diffuse large cell NHL in 1988. Five months later he was admitted to our hospital because of loss of visual acquity and numbness in the right upper and lower extremities. The presence of lymphoma cells in CSF, abnormal shadow in the left frontal lobe on a cranial CT scan and MRI scan, and positive Ga scintigraphy yielded a diagnosis of CNS relapse of NHL. Twenty one whole brain and additional 1.0Gy to the left frontal lobe of irradiation were performed. Eight days later the left tumor disappeared. Neurological remission was obtained and has continued until now.

[Complete remission with MEC regimen of acute myeloid leukemia (M4) secondary to 5-year treatment of non-Hodgkin lymphoma].

A 32-year-old woman was admitted to our hospital with pyrexia and general lymphadenopathy in July 1984. She was diagnosed as having malignant lymphoma (follicular, small cleaved cell), stage IV based on the histological findings of lymph nodes in the neck and bone marrow specimen. She was treated with melphalan orally for 3 years, followed by MACOP-B. She attained partial remission with MACOP-B. Thereafter, she received melphalan or Endoxan orally as maintenance therapy. She developed fever and swelling in the gingivae in October 1989. Peripheral blood showed WBC 80,200/microliters with 7.5% myeloblasts and 85.5% monocytes. Bone marrow aspirate revealed hypercellularity with 47.9% myeloblasts, 46.5% monoblasts and monocytes, which were positive for peroxidase and NSE stains. The karyotype of bone marrow cells showed a 46,XX,t(9;11). The lysozyme in serum was elevated. She was diagnosed having AML (M4). DCMP regimen was initiated but failed to achieve CR. Consequently she received MEC regimen and obtained complete remission, lasting for 6 months. Patients with second leukemia have a low probability of achieving complete remission using conventional chemotherapy. The MEC regimen is thought to be one of the most promising treatments for secondary leukemia.

Treatment of diffuse non-Hodgkin's lymphoma with combined chemotherapy using methotrexate, adriamycin, cyclophosphamide, vincristine, prednisolone and bleomycin (MACOP-B).

Forty-nine previously untreated adult patients with diffuse non-Hodgkin's lymphoma were treated with MACOP-B (methotrexate, adriamycin, cyclophosphamide, vincristine, prednisolone and bleomycin) between December 1986 and December 1990. Forty patients (82%) achieved a complete response (CR), three (6%) a partial response (PR), while four (8%) had either no response or progression of disease, one (2%) patient ceased MACOP-B therapy and received other chemotherapy because of sustained neutropenia, and one patient (2%) died of sepsis during therapy. The factors that adversely affected the CR rate were by stage IV, the presence of B symptoms, the presence of a large mass (greater than 5 cm), and low serum total protein level. The 4-year survival for all 49 patients was 70% and the 4-year disease-free survival (DFS) for the 40 CR patients was 77%. Relapses were higher in patients whose initial serum lactic dehydrogenase (LDH) level was higher than 660 IU/1 (DSF 89% vs. 49%). Toxicity was substantial but acceptable, with neutropenia and mucositis proving to be the most frequent severe side-effects. These preliminary results confirmed the effectiveness of MACOP-B therapy for diffuse non-Hodgkin's lymphoma.