Low doses of arsenic trioxide can induce complete remissions in patients with APL who have relapsed. The clinical response is associated with incomplete cytodifferentiation and the induction of apoptosis with caspase activation in leukemic cells.
PS-341 was well tolerated at 1.04 mg/m(2) on this dose-intensive schedule, although patients need to be monitored for electrolyte abnormalities and late toxicities. Additional studies are indicated to determine whether incorporation of dose/body surface area yields a superior PD model to dosing without normalization. PS-341 showed activity against refractory multiple myeloma and possibly non-Hodgkin's lymphoma in this study, and merits further investigation in these populations.
Induction therapy of APL with all-trans RA and arsenic trioxide is associated with leukocytosis and the RA syndrome. These clinical effects seem to be intrinsically related to the biologic responsiveness and the differentiation process induced by these new agents.
This analysis shows that arsenic trioxide can prolong the QTc interval. However, with appropriate ECG monitoring and management of electrolytes and concomitant medications, arsenic trioxide can be safely administered in patients with relapsed APL.
Arsenic trioxide (As2O3) has recently been used successfully in the treatment of acute promyelocytic leukemia and has been shown to induce partial differentiation and apoptosis of leukemic cells in vitro. However, the mechanism by which As2O3 exerts its antileukemic effect remains uncertain. Emerging data suggest that the endothelium and angiogenesis play a seminal role in the proliferation of liquid tumors, such as leukemia. We have shown that activated endothelial cells release cytokines that may stimulate leukemic cell growth. Leukemic cells, in turn, can release endothelial growth factors, such as vascular endothelial growth factor (VEGF). On the basis of these observations, we hypothesized that As2O3 may interrupt a reciprocal loop between leukemic cells and the endothelium by direct action on both cell types. We have shown that treatment of proliferating layers of human umbilical vein endothelial cells (HUVECs) with a variety of concentrations of As2O3results in a reproducible dose- and time-dependent sequence of events marked by change to an activated morphology, up-regulation of endothelial cell adhesion markers, and apoptosis. Also, treatment with As2O3 caused inhibition of VEGF production in the leukemic cell line HEL. Finally, incubation of HUVECs with As2O3 prevented capillary tubule and branch formation in an in vitro endothelial cell–differentiation assay. In conclusion, we believe that As2O3 interrupts a reciprocal stimulatory loop between leukemic cells and endothelial cells by causing apoptosis of both cell types and by inhibiting leukemic cell VEGF production.
Epigenetic mechanisms underlying tumorigenesis have recently received much attention as potential therapeutic targets of human cancer. We designed a pilot study to target DNA methylation and histone deacetylation through the sequential administration of 5-azacytidine followed by sodium phenylbutyrate (PB) in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Ten evaluable patients (eight AML, two MDS) were treated with seven consecutive daily subcutaneous injections of 5-azacytidine at 75 mg/m 2 followed by 5 days of sodium PB given intravenously at a dose of 200 mg/kg. Five patients (50%) were able to achieve a beneficial clinical response (partial remission or stable disease). One patient with MDS proceeded to allogeneic stem cell transplantation and is alive without evidence of disease 39 months later. The combination regimen was well tolerated with common toxicities of injection site skin reaction (90% of the patients) from 5-azacytidine, and somnolence/fatigue from the sodium PB infusion (80% of the patients). Correlative laboratory studies demonstrated the consistent reacetylation of histone H4, although no relationship with the clinical response could be demonstrated. Results from this pilot study demonstrate that a combination approach targeting different mechanisms of transcriptional modulation is clinically feasible with acceptable toxicity and measurable biologic and clinical outcomes.
All-trans retinoic acid (ATRA) induces a high incidence of complete remission (CR) in patients with acute promyelocytic leukemia (APL); however, the magnitude of this agent's contribution to increased rates of cure of this disease has not yet been established. From 1990 to 1995 we used RA as remission induction therapy in 103 APL patients (73 newly diagnosed and 30 previously treated) who were retinoid-naive and were treated on the basis of initial morphology. Patients whose diagnosis was changed on the basis of the results of molecular testing (n = 13) were withdrawn from RA treatment and given chemotherapy alone. After achieving a CR, previously untreated patients received several cycles of consolidation chemotherapy, usually with idarubicin and cytosine arabinoside. Among individuals whose diagnosis was molecularly confirmed, 54 of 65 new patients (83%) and 25 of 30 previously treated patients (83%) achieved a CR. All induction failures in molecularly diagnosed cases were due either to early death or to premature withdrawal. Median disease-free and overall survival rates recorded for all newly diagnosed patients are currently > 40+ and > 43+ months, respectively. We subsequently examined a subset of 27 newly diagnosed patients treated during the first 2 years of this program whose actual median follow-up period is now > 5 years. Median disease-free and overall survival rates recorded for this group are > 57+ and > 58+ months, respectively; 56% of these patients are alive in first remission. These results significantly exceed those achieved using chemotherapy alone in a historical control group of 80 patients consecutively treated at this center from 1975 to 1990, whose median disease-free and overall survival rates were 11 and 19 months, respectively; only 22% of these patients were alive in first remission at 5 years. Although a high proportion of previously treated patients also achieved a CR after RA treatment, median disease-free and overall survival rates noted for that group were markedly lower (i.e., 7.5 and 10.9 months, respectively). Thus, data from patients whose median follow-up period is now > 5 years have confirmed earlier projections and indicate that the use of RA for remission induction yields an approximately 2.5-fold increase in the proportion of patients who have presumably been cured of this disease.
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