The clinical outlook for adults with acute lymphoblastic leukemia (ALL) has Improved with the use of intensive chemotherapy. Complete remissions (CR) are achieved in 80% of adults but the majority relapse on maintenance chemotherapy and a few exhibit primary resistance to induction therapy. This report compares the various salvage treatments and provides guidance in selecting a regimen with the optimum clinical outcome. Regimens using high-dose ara-C (HDAC) in combination with mltoxantrone, amsacrine, or idarublcin are superior to HDAC alone or with L-asparaginase. The sequential administration of methotrexate and L-asparaginase Is equally effective. The duration of second CR is short for all chemotherapeutic regimens. © 1994 Wiley-Liss, Inc.

Impact of reinduction regimens for relapsed and refractory acute lymphoblastic leukemia in adults.

Summary In acute lymphoblastic leukaemia (ALL) substantial progress has been achieved within the last few years. Complete remission rates up to 95% can now be achieved in children and 70–85% in adults; disease free survival rates are 70 and 30% respectively. To improve results further high dose treatment has been included, particularly to overcome drug resistance and to reach cytostatic levels in the sanctuary sites, such as the central nervous system. High dose cytarabine in combination with other cytostatic drugs, preferentially anthracyclines, seems to be of benefit for high risk adult ALL patients. High dose methotrexate, mostly explored in childhood ALL, is now also included in a variety of combinations in the treatment of adult ALL, but its effectiveness remains to be established. Substantial progress has been achieved in adult T-ALL and B-ALL with survival rates of 40–50%. The optimal form and duration of maintenance therapy in adult ALL is not yet clear but general omission of maintenance leaves patients with an inferior outcome. Which subgroups of adult ALL require maintenance and in what form still requires investigation. In recent adult ALL trials with intensive chemotherapy similar prognostic factors for disease free survival have emerged. Of adverse influence are delayed time to reach CR (more than 4/5 weeks), a high initial white blood cell count, higher age (above 50 or 60 years), and probably the immunological subtypes pre-T-ALL, pre-B-ALL, My + -ALL; of very adverse influence in elderly patients is the karyotype t(9;22) or the corresponding BCR/ABL gene rearrangement. High risk adult ALL patients with one or more of these adverse factors are candidates for allogeneic or autologous bone marrow transplantation in first remission. Whether all adult ALL patients are candidates for BMT in first CR is currently being explored in large prospective randomized trials.

5 Therapy and prognostic factors in adult acute lymphoblastic leukaemia

Gangliosides are complex glycosphingolipids that are the major component of cytoplasmic cell membranes, and play a role in the control of biological processes. Human mesenchymal stem cells (hMSCs) have received considerable attention as alternative sources of adult stem cells because of their potential to differentiate into multiple cell lineages. In this study, we focus on various functional roles of gangliosides in the differentiation of hMSCs into osteoblasts or neuronal cells. A relationship between gangliosides and epidermal growth factor receptor (EGFR) activation during osteoblastic differentiation of hMSCs was observed, and the gangliosides may play a major role in the regulation of the differentiation. The roles of gangliosides in osteoblast differentiation are dependent on the origin of hMSCs. The reduction of ganglioside biosynthesis inhibited the neuronal differentiation of hMSCs during an early stage of the differentiation process, and the ganglioside expression can be used as a marker for the identification of neuronal differentiation from hMSCs.

Role of gangliosides in the differentiation of human mesenchymal-derived stem cells into osteoblasts and neuronal cells

4′-thio-β-d-Arabinofuranosylcytosine (T-araC) exhibits excellent in vivo antitumor activity against a variety of solid tumors despite its structural similarity to β-d-arabinofuranosylcytosine (araC), an agent which is poorly active against solid tumors in vivo. It is of great interest to elucidate why these compounds show a profound difference in antitumor activity. Because deoxycytidine kinase (dCK) is the critical enzyme in the activation of both compounds, here we report the differences in the substrate characteristics with human dCK between these compounds. The catalytic efficiency ( V max/ K m) of araC was 100-fold higher than that of T-araC using either ATP or UTP as the phosphate donor. However, V max values of araC and T-araC were similar when UTP was the phosphate donor. Since UTP is believed to be the true phosphate donor for dCK in intact cells, these data indicated that the rates of phosphorylation of these two compounds at high pharmacologically relevant concentrations would be similar. This prediction was confirmed in intact cell experiments, which supported the hypothesis that UTP is the physiological phosphate donor for dCK phosphorylation in cells. The relative lack of importance of phosphate donor to the phosphorylation of T-araC by dCK revealed important insights into the activation of this compound in human cells at pharmacological doses. These studies indicated that replacement of the 4′-oxygen with sulfur significantly reduced the substrate activity of nucleoside analogs with dCK and that the superior activity of T-araC with respect to araC against solid tumors was not due to superior activity with dCK.

Phosphorylation of 4′-thio-β-d-Arabinofuranosylcytosine and Its Analogs by Human Deoxycytidine Kinase

Thirty-two patients with untreated ALL (n = 26) or lymphoblastic lymphoma (n = 6) between 17 and 65 years of age were treated with a short remission induction course with VP16-213, amsacrine, intermediate dose Ara-C for 6 days, prednisone and intrathecal methotrexate, followed by a consolidation course with vincristine, amsacrine, high dose Ara-C for 4 days, prednisone and intrathecal methotrexate. After subsequent cranial irradiation, no further maintenance was planned. However, some patients underwent an allogenic (n = 5) or autologous (n = 5) bone marrow transplantation after the consolidation treatment. Twenty-three of 32 patients (72%) achieved a complete remission. Ten of 13 patients with T-ALL or lymphoma, six of eight patients with pre-B or common ALL, and seven of 11 patients with B-ALL or Burkitt's lymphoma achieved a complete remission. The median duration of remission was 24 months. Overall survival for the whole group was 35% at 5 years. The disease-free survival was 45% at 5 years. Long-term survival for patients with B or T-ALL was approximately 60%, compared with 15% for those with common or pre B-ALL. Short term intensive courses including intermediate or high dose Ara-C during remission and consolidation treatment lead to results comparable to those obtained with long-term maintenance regimens. Our regimen may be sufficient for patients with T or B-ALL. Larger randomized studies are needed to investigate the relative importance of our observations.

High-dose Ara-C for remission induction and consolidation of previously untreated adults with ALL or lymphoblastic lymphoma

Cytosine arabinoside for induction, salvage, and consolidation therapy of adult acute lymphoblastic leukemia.

Since 1974, umbilical cord blood (CB) has been shown to contain haematopoietic stem cells similar to stem cells from the bone marrow. In 1988, E. Gluckman and her colleagues performed - successfully - the first familial CB transplantation and cured a 5 years old child suffering from Fanconi's anemia. Rapidly, CB banks were organised throughout in the world and thanks to this novel source of haematopoietic stem cells, we can now find a donor for 75 % of the patients requiring a "bone marrow" transplantation. The major benefit of CB as a source of hematopoietic stem cells is its easy access. CB also allows a more significant degree of HLA incompatibility and thus offers an opportunity of transplantation to ethnic minorities for whom no HLA identical donors are available. However, several studies have shown that the number of cells harvested in a CB was closely correlated with the engraftment post transplantation and today, a minimum of 3.7 x 10(7) mononucleated cells/kg is recommended. This required amount of cells is not always reached due to the small volume often harvested from a CB. Therefore, to apply CB transplantations to adults, different approaches are currently being investigated : coinfusion of haploidentical cells, mesenchymal cells, a second CB, or the addition of CB expanded ex-vivo. Among these approaches, double CB transplantation seems nowadays the most promising alternative and ongoing studies should soon inform us whether the duration of aplasia will be improved.

Le sang de cordon : du laboratoire au lit du malade

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Cytosine arabinoside for induction, salvage, and consolidation therapy of adult acute lymphoblastic leukemia.

Le sang de cordon : du laboratoire au lit du malade