Mitsuo Kozuru

A new G-CSF-supported combination chemotherapy, LSG15, for adult T-cell leukaemia-lymphoma : Japan Clinical Oncology Group Study 9303

This phase II trial was performed to evaluate the efficacy of a new granulocyte colony‐stimulating factor (G‐CSF)‐supported multi‐agent chemotherapy protocol, LSG15, for aggressive adult T‐cell leukaemia‐lymphoma (ATL). Ninety‐six previously untreated patients with aggressive ATL were enrolled and grouped as: acute type (58), lymphoma type (28) and unfavourable chronic type (10). Therapy consisted of seven cycles of VCAP (vincristine, cyclophosphamide, doxorubicin and prednisone), AMP (doxorubicin, ranimustine and prednisone) and VECP (vindesine, etoposide, carboplatin and prednisone). G‐CSF was administered during the intervals between chemotherapy until neutrophil reconstitution was achieved. Eighty‐one per cent of the 93 eligible patients responded [95% confidence interval (CI), 71·1–88·1%], with 33 patients obtaining complete response (35·5%) and 42 obtaining partial response (45·2%). The median survival time (MST) after registration was 13u2003months and the median follow‐up duration of the 20 surviving patients was 4·2u2003years (range 2·8–5·6). Overall survival at 2u2003years was estimated to be 31·3% (95% CI, 22·0–40·5%). Grade 4 haematological toxicity of neutropenia and thrombocytopenia were observed in 65·3% and 52·6% of the patients respectively, but grade 4 non‐haematological toxicity was observed in only one patient. LSG15 is feasible with mild non‐haematological toxicity and improved the clinical outcome of ATL patients. MST and overall survival at 2u2003years were superior to those obtained by our previous trials.

Hypomethylation Status of CpG Sites at the Promoter Region and Overexpression of the Human MDR1 Gene in Acute Myeloid Leukemias

Selection of human cells for resistance to vincristine or doxorubicin often induces overexpression of the multidrug resistance 1 gene (MDR1), which encodes the cell surface P-glycoprotein, as a result of gene amplification or transcriptional activation. Moreover, overexpression of the MDR1 gene has been shown to be associated closely with clinical outcome in various hematological malignancies, including acute myeloid leukemia (AML). However, the precise mechanism underlying overexpression of the MDR1 gene during acquisition of drug resistance remains unclear. We recently described an inverse correlation between the methylation status of CpG sites at the promoter region and expression of the MDR1 gene in malignant cell lines. In this study, we expanded this analysis to 42 clinical AML samples. We adapted a quantitative reverse transcription-polymerase chain reaction (RT-PCR) assay for gene expression and a quantitative PCR after digestion by Hpa II for methylation status of the MDR1 gene. We observed a statistically significant inverse correlation between methylation and MDR1 expression in clinical samples. The hypomethylation status of the MDR1 promoter region might be a necessary condition for MDR1 gene overexpression and establishment of P-glycoprotein-mediated multidrug resistance in AML patients.

Deoxycoformycin-containing combination chemotherapy for adult T-cell leukemia-lymphoma: Japan Clinical Oncology Group Study (JCOG9109).

Aggressive adult T-cell leukemia-lymphoma (ATL) generally has a very poor prognosis. Deoxycoformycin (DCF, pentostatin), an inhibitor of adenosine deaminase, has shown promising therapeutic efficacy for ATL. To develop a new effective therapy against aggressive ATI., we carried out a multicenter phase II study of DCF-containing combination chemotherapy. Sixty-two previously untreated patients with ATL (34, 21, and 7 patients with diseases of the acute, lymphoma, and unfavorable chronic types, respectively) were enrolled, but 2 were ineligible because they were judged to be favorable chronic types. A regimen of 1 mg/m2 vincristine intravenously on days 1 and 8, 40 mg/m2 doxorubicin intravenously on day 1,100 mg/m2 etoposide intravenously on days 1 through 3, 40 mg/m2 prednisolone orally on days 1 and 2, and 5 mg/m2 DCF intravenously on days 8,15, and 22 was administered every 28 days for 10 cycles unless disease progression or toxic complications occurred. Fifty-two percent of 60 eligible patients responded (95% confidence interval [CI], 38%-65%), with 17 patients (28%) achieving a complete response (CR) (95% CI, 17%-41%) and 14 achieving a partial response. The CR rate was inferior to those of both the previous Japan Clinical Oncology Group (JCOG) study (JCOG8701, 43%), a 9-drug combination chemotherapy of the second generation, and the subsequent JCOG9303 study (35%), a granulocyte colony-stimulating factor-supported, dose-intensified, 9-drug regimen. The median survival time of the 60 eligible patients in JCOG9109 was 7.4 months, and the estimated 2-year survival rate was 15.5%; these results were identical with those of JCOG8701 but inferior to those of JCOG9303. Grade 4 neutropenia and infection of grade 3 or greater were frequent (67% and 22%, respectively), and treatment-related death was observed in 4 patients (7%), scpticcmia in 2, and cytomcgalovirus pneumonia in 2. We conclude that DCF-containing combination chemotherapy is not a promising regimen against aggressive ATL.

Parvovirus B19‐associated haemophagocytosis in Evans syndrome: aplastic crisis accompanied by severe thrombocytopenia

Summary. A 36‐year‐old man who had been treated for Evans syndrome (ES) developed an aplastic crisis caused by acute human parvovirus B19 (HPV) infection. Profound thrombocytopenia (8·0 × 109/l) followed with a sudden increase in platelet‐associated IgG (PAIgG) (1376·9 ng/107 plts). Bone marrow examination revealed a considerable number of haemophagocytic histiocytes without any disturbance of megakaryopoiesis. To our knowledge this is the first case of aplastic crisis with virus‐associated haemophagocytosis in a patient with ES, which provides an interesting insight into the mechanisms for thrombocytopenia in HPV infection.

Successful treatment of a patient with cardiac lymphoma who presented with a complete atrioventricular block

A patient with primary cardiac lymphoma, which is very rare, generally is regarded to have a poor prognosis. We herein report a patient with cardiac lymphoma who was treated successfully by systemic chemotherapy and radiotherapy using a pacemaker to control the complete atrioventricular (A‐V) block. A 70‐year‐old man had a syncope caused by a complete A‐V block. An echocardiogram, a computed tomographic scan, and magnetic resonance imaging of his chest showed a cardiac tumor. At this time, a biopsy of the cardiac tumor disclosed malignant lymphoma (diffuse large cell type, B cell type). The patient was thus treated with systemic chemotherapy and radiotherapy and, as a result, achieved a complete remission with a disappearance of the A‐V block. Recently, several successful outcomes involving primary cardiac lymphoma have been reported because of the progress in diagnostic techniques including echocardiography, computed tomographic scanning, and magnetic resonance imaging, as well as improvement in the therapy of malignant lymphoma. Our clinical experience indicated that an early and accurate diagnosis combined with the appropriate therapy can thus help in obtaining a long survival in patients with primary cardiac lymphoma. Am. J. Hematol. 59:171–174, 1998.

Soluble fas in the serum of patients with non-Hodgkin's lymphoma : Higher concentrations in angioimmunoblastic T-cell lymphoma

The soluble form of Fas (sFas) can block apoptosis induced by the Fas ligand in vitro. A recent report demonstrated that mice injected with sFas displayed autoimmune features. Therefore, an elevated serum concentration of sFas may be associated with lymphoproliferation and autoimmune diseases. We measured the serum concentrations of sFas in 77 patients with non‐Hodgkins lymphoma (NHL) [8 angioimmunoblastic T‐cell lymphoma (AIL), 12 T‐cell NHL, 53 B‐cell NHL, and 4 natural killer‐cell NHL]. Elevated concentrations of sFas were detected only in AIL, which is frequently accompanied by autoimmune diseases (P < 0.005 compared with age‐matched controls). A possible association of sFas and autoimmune features in AIL is discussed. Am. J. Hematol. 58:334–336, 1998.

The Differences between Lymphoma and Leukemia Type of Adult T-cell Leukemia

The difference between lymphoma type and leukemia type of adult T-cell leukemia (ATL) were analysed with 102 Japanese patients all positive for human T-cell leukemia virus type I (HTLV-I) antibody. They were classified into three groups on findings at first medical examination: lymphoma type cases, leukemia type cases, and mixed type (leukemia type plus lymphadeno-pathy) cases. Lymphoma type patients had several or more enlarged lymph nodes the largest of which was greater than 1 cm in diameter and with practically no abnormal lymphocytes (ATL. cells), which are characteristic of ATL, in the peripheral blood. Leukemia type patients had 10% or more ATL cells in the peripheral blood and had no detectablle lymphadenopathy Lymphoma type patients often complained of detectable lymphadenopathy, while leukemia type patients complained frequently of general fatigue and skin eruption. Mixed type patients more frequently had signs and symptoms which were characteristic of both types: lymphadenopathy and 10% or more ATL cells in the peripheral blood. Mixed type: ATL had a poorer prognosis than either lymphoma type or leukemia type. The median survival time was 3 months for mixed type patients, 10.5 months for lymphoma type patients, and 13.5 months for leukemia type patients. Complications and causes of death have also been touched upon. Clinicians are thus advised to consider ATL patients separately according to their clinical manifestations.

Genotypic and cytogenetic study of acute myelocytic leukemia and chronic myelocytic leukemia in blast crisis : specific δ rearrangement pattern does not involve Jδ gene locus

Abstract We have analysed the configuration of immunoassociated genes and the karyotypes of 30 patients with acute myelocytic leukemia (AML) and 10 with chronic myelocytic leukemia in blast crisis (CML-BC). In AML, the frequencies of T-cell receptor (TcR) β, γ, and δ chain and immunoglubulin heavy and light chain gene rearrangements were 4.2%, 19%, 8%, 10.7% and 10.5%, respectively. In CML-BC, they were 10%, 20%, 40%, 50% and 0%, respectively. Nine patients had abnormalities in chromosome 2, 7 or 14, upon which immunoassociated genes are located. There seems to be no apparent relationship between these chromosome abnormalities and gene rearrangements. In all patients but one (5/6), the δ rearrangement was accompanied by other immunoassociated gene rearrangements. Molecular size analysis revealed specific δ rearranged band(s) (19.5 kb-BamHI and/or 6.9 kb-EcoRI), as commonly detected in B-acute lymphocytic leukemia (ALL). All the patients with the δ rearranged band, however, had a germline configuration of J δ gene loci, suggesting a DD or V(D)D (probably V δ 2(D)D) pattern. This study also indicates that the δ rearrangement is specific in AML or CML-BC and distinct from that in early T leukemia/lymphoma.

Telomerase activity in myeloma cells is closely related to cell cycle status, but not to apoptotic signals induced by interferon-α

Telomeres, G-rich structures at the ends of chromosomes are essential for maintaining chromosomal integrity. Most tumor cells contain telomerase, a ribonucleoprotein that elongates telomeric repeats, and it plays an essential role in indefinite proliferation. To better understand regulatory mechanisms of telomerase, in relationship with apoptosis and the cell cycle, we examined telomerase activity in PCM6, an interleukin-6 (IL-6)-responsive, interferon-alpha (IFN-alpha)-sensitive multiple myeloma cell line, using a PCR-based assay. When PCM6 cells were cultured in serum-free media, the addition of IFN-alpha resulted in apoptosis of the cells, but with no influence on telomerase activity. When IFN-alpha was added to the culture with serum plus rIL-6 after serum deprivation, G1-S transition was inhibited and telomerase activity was lower compare to findings in culture with no IFN-alpha. Dose response experiments of rIL-6 and IFN-alpha, and the measurement of telomerase activity of sorted cells in S-phase using CD71, demonstrated a higher activity of telomerase in the samples which contained a larger proportion of cells in S-phase. These data indicate that regulation of telomerase activity is closely related to cell cycle status, in particular cells in S-phase have an high telomerase activity. While telomeres play an important role in cellular senescence, the regulation of telomerase is independent from apoptotic signals induced by IFN-alpha in myeloma cells.

Regulation of erythropoietin and burst-promoting activity production in patients with aplastic anemia and iron deficiency anemia.

To clarify the control mechanism of production of erythropoietic growth factors in anemic states, we compared erythropoietin (Epo) and burst-promoting activity (BPA) in patients with aplastic anemia and iron deficiency anemia, using in vitro erythroid progenitor assays. Although serum levels of Epo activity increased in the presence of anemia, the rise was more marked in patients with aplastic anemia. BPA was high only in the sera of aplastic anemia patients. Serum levels of BPA of patients with aplastic anemia negatively correlated with hemoglobin concentrations, while those of patients with iron deficiency anemia did not correlate. In 2 patients with aplastic anemia who responded well to androgen therapy, serum levels of Epo activity and BPA decreased after the hemopoiesis had recovered. These results suggest that serum levels of BPA do not rise in response to anemia only. The elevated BPA levels in sera in cases of aplastic anemia are probably related to a reduction in the number of hemopoietic stem cells. Moreover, we observed that BPA in bone-marrow-conditioned medium (BMCM) from patients with severe aplastic anemia increased more than in the BMCM from patients with severe iron deficiency anemia. Therefore, our findings suggest that the enhanced BPA production depends on a decrease in hemopoietic precursors rather than the anemic state.