High-dose methotrexate in the treatment of adult acute lymphoblastic leukemia

Abstract

The application of high-dose treatment elements has an increasing importance in the therapy of acute lymphoblastic leukemia (ALL). High-dose methotrexate (HDMTX) has been introduced in clinical trials more than 20 years ago, since it has several theoretical advantages compared to conventional dose methotrexate. These trials revealed that the efficacy and toxicity of HDMTX depends on features such as dose level, infusion time, combination regimen and schedule of leucovorin rescue. Particularly the application of controlled leucovorin rescue and improved supportive care enabled the application of increasing doses of HDMTX in the treatment of childhood and adult ALL within a variety of schedules and at dose levels mostly ranging between 0.5 g/m2 and 5.0 g/m2. In childhood ALL, first devised to replace CNS irradiation in the prophylaxis of CNS relapse HDMTX has contributed to the reduction of bone marrow relapses particularly in low risk B-lineage ALL. In addition it proved to be an effective therapy element for prophylaxis and treatment of CNS disease. At least in low risk ALL CNS irradiation could be safely replaced by repeated cycles of HDMTX with additional intrathecal therapy. In adult ALL only few of the successful treatment approaches with HDMTX have been investigated up to now. The results indicate that HDMTX has a beneficial effect with regard to overall outcome in adult B-lineage ALL. It provides effective CNS prophylaxis in combination with intrathecal therapy. In mature B-ALL HDMTX proved to be one of the most effective treatment elements and contributed to an impressive improvement of outcome in this subgroup. For T-ALL however sufficient data do not exist either in childhood or in adult ALL. Since HDMTX is an effective treatment element with manageable acute and long-term toxicity, its role in the management of adult ALL should be explored more intensively.

Isolated extramedullary relapse of acute lymphoblastic leukaemia after allogeneic bone marrow transplantation

“…In fact, isolated extramedullary relapses of leukaemia with noninvolved marrow after allogeneic BMT have been consistently, albeit infrequently, reported. 6,10,[14][15][16] These reports, together with the present case, would support a possible differential favourable effect of GVL on the marrow as compared with other peripheral sites.…”

“…However, there may be practical significance in elucidating these mechanisms. Sanctuary sites might need to be tackled with additional therapy before BMT, such as CNS prophylaxis; 16 while the GVL effect might need to be augmented in high risk cases. 17 Finally, it is important to recognise that extramedullary relapses with non-involved marrow after BMT might be amenable to a combination of local treatment, systemic chemotherapy and therapy that aims at augmentation of GVL, 6,10,12,[14][15][16] and therefore consistent with prolonged survival.…”

Glucarpidase (Carboxypeptidase G2) Intervention in Adult and Elderly Cancer Patients with Renal Dysfunction and Delayed Methotrexate Elimination After High-Dose Methotrexate Therapy

“…High-dose methotrexate (HD-MTX) is frequently used in various malignancies, including acute lymphoblastic leukemia, osteosarcoma, central nervous system (CNS) lymphoma, and leptomeningeal cancer [1][2][3][4]. With leucovorin rescue and standard supportive care, HD-MTX carries a low risk for severe treatment-related toxicity.…”

A review of physiological and metabolic effects of essential amino acids

“…Unlike humans, some microorganinsms synthesize folic acid directly. In humans, methotrexate inhibits the conversion of folic acid to its active form and is a useful regimen for patients with acute lymphocytic leukemia (Fleisher, 1993;Gokbuget and Hoelzer, 1996). Histidine has effects on a variety of organisms and physiological systems.…”