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.     

Thrombopoietin-producing hepatocellular carcinoma

A 66-year-old man with hepatocellular carcinoma (HCC) showed marked thrombocytosis (110.7 x 10(4)/microl). Bone marrow (BM) aspirates demonstrated an increase of mature megakaryocytes (MgK). The serum thrombopoietin (TPO) level was increased to about 100-fold that of the normal level in the terminal stage. However, the platelet count gradually decreased to 13.5 x 10(4)/microl. The autopsy specimen revealed normoplastic BM with decreased MgK, mainly consisting of the immature type, and it was negative for tumor cells. Liver specimen showed markedly fatty metamorphosis. Immunohistochemical staining of TPO demonstrated that hepatocytes were weakly stained and HCC cells strongly stained, suggesting TPO-producing HCC.     

Combination chemotherapy of carboplatin and cytosine arabinoside for high-risk leukemia: A pilot study

Fourteen patients with high-risk leukemia (six with relapsed AML, three with relapsed ALL, one with AML-M0, four with CML in myeloid blastic crisis) were treated with a combination chemotherapy of carboplatin (200–300 mg/m²/day) and cytosine arabinoside (100 mg/m²/day) by 24 h continuous infusion for 5–7 days. Five patients (35.7%) achieved complete remission including two patients complicated with myelofibrosis (one with AML-M0 and one with CML in myelo-megakaryocytic crisis). Thirteen patients had nausea and vomiting, five patients had severe, prolonged neutropenia for which it was necessary to administer granulocyte colony-stimulating factor and six patients had severe thrombocytopenia. We concluded that this regimen is effective for the treatment of high-risk leukemia.     

Deletion of Src Homology 3 Domain Results in Constitutive Activation of Tec Protein-Tyrosine Kinase

Tec protein-tyrosine kinase (PTK) is the prototype of a new subfamily of non-receptor type PTKs, and is abundantly expressed in hematopoietic tissues. We have revealed that Tec is inducibly tyrosine-phosphorylated and activated by stimulation with a wide range of cytokines. To get more insight into the signaling mechanism through Tec, we have generated a constitutively active form of Tec PTK. Deletion of the Src homology (SH) 3 domain gave rise to a hyperphosphorylated and activated Tec kinase (TecΔSH3). The activity of TecΔSH3 was confirmed in 293 cells, as well as in cytokine-dependent hematopoietic cells (BA/F3). TecΔSH3 should be a useful tool to study the in vivo substrates of Tec PTK.     

Multipotent and Committed CD34+ Cells in Bone Marrow Transplantation

In order to study the role of CD34⁺ cells in hematological recovery following bone marrow transplantation (BMT), bone marrow cells stained with HPCA-1 (CD34) and MY-9 (CD33) monoclonal antibodies were analyzed by using a fluorescence-activated cell sorter on or about days 14 and 28, as well as at later times, following BMT in 6 recipients. Single cell cultures of CD34⁺ cells were also performed to evaluate their in vitro hematopoietic function. CD34⁺ cells were detectable in bone marrow cells on day 14. More than 80% of CD34⁺ cells co-expressed the CD33 antigen, and macrophage (Mac) colony-forming cells predominated among total colony-forming cells of CD34⁺ cells. In normal bone marrow cells, CD34⁺, CD33⁺ cells amounted to about 40% of CD34⁺ cells, and the incidences of erythroid bursts, granulocyte/macrophage (GM) colonies, and Mac colonies were similar to each other. After more than 10 weeks, CD34⁺, CD33⁻ cells gradually recovered, as erythroid burst colony-forming cells increased following GM colony-forming cells. This phenomenon was well-correlated with the time course of peripheral blood cell recovery. CD34⁺, CD33⁺ cells as committed progenitors and CD34⁺, CD33⁻ cells as multipotent stem cells have distinctive biological behaviors in BMT.     

Philadelphia chromosome positive B-cell type malignant lymphoma expressing an aberrant 190 kDa bcr-abl protein

The Philadelphia (Ph) chromosome translocation, t(9:22) (q34;q11) is found in some acute lymphoid leukaemias (ALL) and acute myeloid leukaemias (AML). Although cytogenetically all pH chromosomes appear similar, the 22q11 breakpoints found in acute leukaemias are of two kinds, those within the major breakpoint cluster region (Mbcr-1) of the BCR gene as found in chronic myelogenous leukaemia (CML), and those within the first intron of this gene. In the former group the molecular events are the same as those found in CML, p210 bcr-abl, encoded by 8.5 kb mRNA; however, a new aberrant protein, p190 bcr-abl, is found in the latter group. Ph translocation is also found in a few cases with malignant lymphoma, but it has not been characterized at the molecular level. We describe here a non-Hodgkin's lymphoma case with primary splenic presentation, which showed a complex Ph translocation. Neoplastic cells were of a B-cell origin (HLA-DR+, sIgM+, sIg lambda +, CALLA-). Molecular studies revealed the expression of p190 bcr-abl with no Mbcr-1 rearrangement. Our case indicates that the same Ph translocation as seen in acute leukaemias can be found in haematologic disorders other than leukaemias, suggesting that a c-abl gene activating mechanism may be involved in the pathogenesis of wide spectrum of haematologic malignancies.     

Differentiation of human leukemia cells and its usefulness for clinical diagnosis

Various chemical inducers have effects on the induction of terminal differentiation of human myelogenous leukemia cell lines. We studied morphological and functional changes of human leukemia cells freshly obtained from patients using 12-O-tetradecanoyl phorbol-13-acetate (TPA), retinoic acid (RA) or dimethyl sulphoxide (DMSO). The myeloid leukemia cells cultured with TPA became adherent to plastic culture dishes, and then developed macrophage-like morphology with long filamentous pseudopods within 48 h incubation. They showed marked enhancement of the ability to phagocytose latex particles. But these acquired properties did not always parallel each other, suggesting that the mechanism of functional maturation of leukemic cells induced by chemical agents was not identical with that of morphological changes. On the other hand, the lymphoid leukemia cells did not show morphological and functional changes when cultured with the above inducers. It is suggested that exposure of leukemic cells to TPA for relatively short times (12–24 h) may be useful for determining whether they are of myeloid or lymphoid origin. These characteristic changes were also observed in leukemic cells from the myeloid or lymphoid crisis of chronic myelogenous leukemia.     

Proliferative Effect of Human Granulocyte Colony-stimulating Factor on Blast Cells of Acute Promyelocytic Leukemia

The effect of human granulocyte colony-stimulating factor (G-CSF) on leukemic cells of acute promyelocytic leukemia (APL) was examined. Mononuclear cells obtained from bone marrow cells containing more than 90% blasts from seven APL patients were incubated in the presence of G-CSF using semisolid and liquid culture systems. On day 7, the cells from all the patients produced many clusters consisting of 8–40 cells. These cells appeared to be promyelocyte-like blast cells in four patients and had differentiated to more mature neutrophils in three patients. On day 14, the number of clusters decreased except for two patiens. Blast cells from the two patients showing the increase of blast clusters could proliferate in a liquid culture containing G-CSF. Blast cells cultured for 14 days formed many secondary cultures after replating on a methylcellulose medium. Moreover, chromosomal analyses of blasts cultivated in the presence of G-CSF for 7 days showed t(15;17) in all metaphases in one patient. It appears that the leukemic cells from APL patients could proliferate in the presence of G-CSF.