Treatment of Acute Promyelocytic Leukemia with Single-Agent Arsenic Trioxide

It is well recognized that arsenic trioxide (ATO) is an efficacious agent for the treatment of acute promyelocytic leukemia (APL). Use of single agent ATO in the treatment of APL leads to remissions which are durable in the majority. ATO is probably the most effective single agent in the treatment of APL and there have been very few reports of primary resistance. It has been used both as a single agent and in combination with other conventional drugs to treat APL. Use of ATO is the accepted standard of care in the management of relapsed APL, where it is often used effectively as a bridge to a stem cell transplant. However, its role in newly diagnosed APL remains controversial. ATO probably has multiple mechanisms of action. Better understanding of its mechanisms of action/s is likely to lead to more rationale use of this agent or its derivatives either alone or in combination with other drugs. There is limited data on the kinetics of leukemia clearance and normal haematopoietic recovery after the administration of single agent ATO for the treatment of APL, preliminary data suggests that it is likely to be different from conventional therapy. There have been a number of concerns of the potential short and long term toxicity of this agent. Most such concerns arise from the toxicity profile noted in people exposed to long term arsenic exposure in the environment. With the therapeutic doses and schedules of administration of ATO in the treatment of malignancies the overall toxicity profile has been favorable. In a resource constrained environments the use of a single agent ATO based regimen is a realistic and acceptable option to treat almost all patients. In the developed world it has the potential in combination with other agents to improve the clinical outcome with reduction of dose intensity of chemotherapy and remains an option for patients who would not tolerate conventional therapy. In this review we focus on the use of single agent ATO for the treatment of APL and summarize our experience and review the literature

Apolipoprotein M attenuates anthracycline cardiotoxicity and lysosomal injury

Apolipoprotein M (ApoM) binds sphingosine-1-phosphate (S1P) and is inversely associated with mortality in human heart failure (HF). Here, we show that anthracyclines such as doxorubicin (Dox) reduce circulating ApoM in mice and humans, that ApoM is inversely associated with mortality in patients with anthracycline-induced heart failure, and ApoM heterozygosity in mice increases Dox-induced mortality. In the setting of Dox stress, our studies suggest ApoM can help sustain myocardial autophagic flux in a post-transcriptional manner, attenuate Dox cardiotoxicity, and prevent lysosomal injury

Metabolic adaptation drives arsenic trioxide resistance in acute promyelocytic leukemia.

Acquired genetic mutations can confer resistance to arsenic trioxide (ATO) in the treatment of acute promyelocytic leukemia (APL). However, such resistance-conferring mutations are rare and do not explain most disease recurrence seen in the clinic. We have generated stable ATO-resistant promyelocytic cell lines that are also less sensitive to ATRA and the combination of ATO and ATRA compared to the sensitive cell line. Characterization of these in-house generated resistant cell lines showed significant differences in immunophenotype, drug transporter expression, anti-apoptotic protein dependence, and PML-RARA mutation. Gene expression profiling revealed prominent dysregulation of the cellular metabolic pathways in these ATO resistant APL cell lines. Glycolytic inhibition by 2-DG was sufficient and comparable to the standard of care (ATO) in targeting the sensitive APL cell line. 2-DG was also effective in the in vivo transplantable APL mouse model; however, it did not affect the ATO resistant cell lines. In contrast, the resistant cell lines were significantly affected by compounds targeting the mitochondrial respiration when combined with ATO, irrespective of the ATO resistance-conferring genetic mutations or the pattern of their anti-apoptotic protein dependency. Our data demonstrate that the addition of mitocans in combination with ATO can overcome ATO resistance. We further show that this combination has the potential in the treatment of non-M3 AML and relapsed APL. The translation of this approach in the clinic needs to be explored further

Comparison of clinical outcomes of patients with relapsed acute promyelocytic leukemia induced with arsenic trioxide and consolidated with either an autologous stem cell transplant or an arsenic trioxide–based regimen

In patients with relapsed acute promyelocytic leukemia (APL), the best consolidation regimen following induction of remission with arsenic trioxide (ATO) remains to be defined. Since January 2000, 37 patients with relapsed APL were treated at our center. The median age was 34 years (range, 6-57 years), and there were 20 males (54.1%). The median duration of first remission was 20.3 months (range, 2.9-81.2 months). Relapse was treated with single-agent ATO in 22 patients (59.5%), ATO+ATRA in 5 patients (13.5%), and ATO+ATRA + anthracycline in 10 patients (27%). Thirty-three patients (89%) achieved molecular remission after induction and a consolidation course. Fourteen patients opted to undergo autologous stem cell transplantation (SCT), and the remaining 19 patients received monthly cycles of ATO as a single agent (n=13) or ATO+ATRA (n=6) for 6 months. At a median follow-up of 32 months, the 5-year Kaplan-Meier estimate of event-free survival (EFS) was 83.33% ± 15.21% in those who underwent autologous SCT versus 34.45% ± 11.24% in those who did not (P=.001; log-rank test). Following remission induction with ATO-based regimens in patients with relapsed APL, consolidation with autologous SCT is associated with a significantly superior clinical outcome compared with ATO- and ATO+ATRA–based maintenance regimens

Spectrum of BCR-ABL kinase domain mutations in patients with chronic myeloid leukemia from India with suspected resistance to imatinib-mutations are rare and have different distributions

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