Recent Trends in the Treatment and Prognosis of Adult Leukemia with Characteristics of Patients in Japan: Transition during the Fifteen Years from 1971 to 1985

Patients with acute (2,569) and chronic (957) leukemia diagnosedat 19 institutes took part in the study on the "MultidisciplinaryTreatment of Leukemia" between 1971 and 1985 and were investigatedretrospectively. By dividing the 15 years into three five-yearperiods, we were able to compare patient ratios in the differentperiods. The proportions of acute to chronic leukemia casesshowed no obvious change; however, the proportions of casesdiagnosed as acute lymphocytic leukemia in acute leukemia showeda significant increase. The main chemotherapeutic drugs usedduring the three time periods were cytarabine or its analogues,the anthracyclines, 6-mercaputopurine and prednisolone, againstacute myelogenous leukemia, and the vinca alkaloids, prednisoloneand the anthracyclines against acute lymphocytic leukemia. Therate of complete remission from acute myelogenous leukemia mademarked progress, from 45.1% during 1971–1975 to 62.3%during 1981–1985, but that of acute lymphocytic leukemiashowed no significant progress, being 65% during 1971–1975and 69.7% during 1981–1985. The durations of remission,however, and the survival times for patients with acute lymphocyticleukemia, as well as for those with acute myelogenous leukemia,became significantly longer over the three periods. Median survivaltimes from chronic myelocytic leukemia were 37–40 mo inall three periods, showing no progress. There was a better prognosisin cases of chronic myelocytic leukemia with, than without,Philadelphia chromosome. Except for a low incidence of chroniclymphocytic leukemia in Japan, adult leukemia patients' characteristicsand prognoses seem to be almost the same in Japan as in theU.S.A. and Europe.     

Lithium chloride inhibits thrombin-induced intracellular calcium mobilization in C6 rat glioma cells

In this study, the authors have demonstrated the effect of lithium, a typical mood stabilizer, on thrombin-evoked Ca2+ mobilization in C6 cells to elucidate the action mechanisms of the drug. Thrombin-induced Ca2 mobilization was reduced 24 hr after 1 or 10 mM lithium chloride (LiCl) pretreatment. The Ca2+ rise was reduced in a time-dependent manner, and the significant inhibition was observed 9 hr pretreatment with 10 mM LiCl. On the other hand, pretreatment of the cells with 10 mM LiCl for 24 hr did not alter the amount of Galphaq/11 significantly. Pretreatment with 10 mM LiCl for 24 hr failed to reduce the 5-HT-induced Ca2+ mobilization or to affect the desensitization of the 5-HT signal. Finally, thrombin-elicited Ca2+ rise was markedly inhibited in the presence of 0.05 U/ml plasmin, however, the Ca2+ rise was not further attenuated in the presence of plasmin in C6 cells pretreated with LiCl for 24 hr. These results indicate that pretreatment with LiCl attenuated thrombin-evoked intracellular Ca2+ mobilization in plasmin sensitive manner in C6 rat glioma cells. Thus, it is important to investigate the effect of lithium on thrombin-induced cellular responses to clarify the action mechanism of lithium in relation to some abnormality in thrombin-evoked Ca2+ rise observed in bipolar disorders.     

Phase I study of cladribine (2-chlorodeoxyadenosine) in lymphoid malignancies. Cladribine Study Group

Cladribine (2-chlorodeoxyadenosine;) is a purine analogue with clinical activity against hairy cell leukemia, chronic lymphocytic leukemia and indolent lymphoma. To clarify the toxicity profiles of cladribine, we conducted a phase I and pharmacological study of cladribine with a schedule of seven-day continuous intravenous infusion every 28 days up to a maximum of three cycles. We enrolled 10 previously-treated patients with various lymphoid malignancies. No dose-limiting toxicity (grade 4 hematologic and/or grade 3 or more non-hematologic) was observed in the three patients who received 0.06 mg/kg/day (Level 1). Of the seven patients who received 0.09 mg/kg/day (Level 2), one patient developed grade 4 hypoxemia and grade 4 thrombocytopenia, and another developed grade 4 neutropenia. Of the seven patients treated at Level 2, one with cutaneous T-cell lymphoma attained complete remission, and one with mantle cell lymphoma, one with chronic lymphocytic leukemia and one with adult T-cell leukemia-lymphoma attained partial remission. A pharmacokinetic analysis of the seven patients without leukemic cells showed that their area under the concentration versus time curves of plasma cladribine increased dose-dependently from 2661.3 +/- 300.4 nM x h at Level 1 (n = 3) to 3411.3 +/- 341.0 nM x h at Level 2 (n = 4) (P = 0.034). We conclude that the recommended phase II dose of cladribine (0.09 mg/kg/day as a seven-day continuous i.v. infusion) in Caucasian patients can be safely administered to Japanese patients. The encouraging results prompted us to plan subsequent phase II studies of cladribine against adult T-cell leukemia-lymphoma, hairy cell leukemia and indolent lymphoma.      

Malignant lymphoma antigen expressed in nude mouse tumor cells derived from carcinogen-transformed Bloom's syndrome B-lymphoblastoid cell lines

From nude mouse tumors, in which malignantly transformed Bloom's syndrome (BS) B-lymphoblastoid cell lines were successfully transplanted into s.c. tissues, we have detected strong expression of malignant lymphoma (ML)-associated antigen on the cell surface, by using diluted sera of ML patients and indirect immunofluorescence. Even though carcinogen-treated BS B-lymphoblastoid cell lines expressed various types of cancer antigens (ML, ovarian cancer, stomach cancer, lung cancer, liver cancer, etc.) on the cell membrane as a mixed population (Y. Shiraishi and H. Soma, Proc. Natl. Acad. Sci. USA, 85:8211-8215, 1988), the finding that BS malignant cells originating from nude mouse tumors expressed specific ML-associated antigen seemed significant for ML diagnosis. BS nude mouse tumors were successively transplantable from nude mice to nude mice (100%). Histopathological studies using an electron microscope demonstrated that most tumor cells in s.c. tissues of nude mice were lymphoid malignant cells. Gel electrophoresis and Western blotting analyses demonstrated that the antigen which characterized ML was a single band (Mr 97,000) and did not cross-react with the sera of other cancer patients or with normal sera. Chromosome analysis showed that the cell clones with ML-associated antigen had marker chromosomes involving t(6;?)(p25;?),t(9;?)(q34;?), del(10)(p13),t(12;14)(q24;q11). The expression of ML-associated antigen was also discussed in relation to the marker chromosomes.     

Detection of t(3 ; 21) (q26 ; q22) with AML1/EVI1 mRNA during progression of myelodysplastic syndrome to acute myeloid leukemia]

A 74-year-old woman had myelodysplastic syndrome (MDS) in 1986. In June 1994, she suffered exacerbation of pancytopenia with no chromosomal abnormalities, but AML1/EVI1 chimeric mRNA was detected by RT-PCR. Two months later, an increase in bone marrow blasts (5%) was noted, and chromosomal analysis detected t(3 ; 21) (q26 ; 22), del(7) (q22), del(11) (q23). In 1995, the marrow blasts increased to 30% and the patient died of disease progression. The AML1/EVI1 gene has been shown to cause blast crisis in chronic myelogenous leukemia. This case suggested that the AML1/EVI1 gene may be involved in the progression of MDS together with del(7) (q22) and del(11) (q23).     

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 ATL, 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%), septicemia in 2, and cytomegalovirus pneumonia in 2. We conclude that DCF-containing combination chemotherapy is not a promising regimen against aggressive ATL.     

i(17q) appearing in acute phase in Ph1-negative, BCR-negative CML]

A 36-year-old woman was referred to our hospital because of splenomegaly in February 1989. The leukocyte count was 55,500/microliter without hiatus leukemicus. The leukocyte alkaline phosphatase score was low (29). The bone marrow showed myeloid hyperplasia (24.8% myeloblasts) but no dysplastic change. The karyotype of the bone marrow cells was 46, XX and a diagnosis of Ph1 (-) CML was made. Treatment with VCR, 6MP and prednisolone made 7-month duration chronic phase, but the abnormal karyotype.[46, XX, i(17q)] gradually increased to 100% of bone marrow cells. The patient died in June 1990. The evidence that not only a BCR rearrangement but also messages of BCR/ABL fusion gene were negative made us able to differentiate this case from Ph1(-), BCR(+) CML. The addition of an i(17q) results in partial monosomy of 17q (17q13;p53 gene) and partial trisomy of 17q (17q11.2-12;G-CSF gene). We examined the rearrangement of p53 gene and G-CSF-dependent tumor cell growth in vitro, demonstrating one allelic loss of p53 gene and independent cell growth on G-CSF respectively. It is thought that in Ph1 (-), BCR (-) CML as well as in Ph1 (+) CML, an i(17q) is related to the progression but not to the initiation of these leukemias. However the precise mechanism, including p53 gene inactivation by point mutation, is still to be elucidated.     

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.