β-Catenin and AKT are promising targets for combination therapy in acute myeloid leukemia

In this study, we confirmed that combining HHT with ACR can result in synergistic cytotoxicity to AML cells in vitro and in vivo. Combining HHT and ACR simultaneously inhibited PI3K/AKT and WNT/β-catenin signaling in AML cells. Significant increases in growth inhibition and apoptosis were induced by an AKT inhibitor when the WNT3A gene of THP-1 cells was silenced. HHT + ACR could synergistically induce the apoptosis of CD34⁺/CD38⁻ primary AML cells. These results highlight β-catenin and AKT are promising targets for combination therapy for AML.     

Monitoring minimal residual disease in acute myeloid leukemia: ready for prime time?

Predicting the outcome of therapy in patients with acute myeloid leukemia (AML) is currently necessary for making treatment decisions. Pretreatment covariates, such as clinical and molecular predictors, have helped identify which patients are more or less likely to survive their disease using the currently available regimens. Progress in establishing optimized flow cytometry and quantitative polymerase chain reaction assays for detecting minimal residual leukemia has provided new potential tools for predicting outcome. However, the most important next step in using these techniques toward personalized treatment of AML would be developing effective and safe strategies for eradicating the residual leukemic cells that are likely chemoresistant. With further refinement and standardization of the assays, and the development of novel, effective, and molecularly targeted agents, monitoring of minimal residual disease is likely to be incorporated into AML guidelines.     

Who benefits from maintenance therapy in acute promyelocytic leukemia?

Acute promyelocytic leukemia (APL) is remarkable for its upfront mortality rate from disseminated intravascular coagulation and its high cure rate with therapy. Although induction and consolidation regimens continue to evolve, newer approaches combine an anthracycline with or without cytarabine and the highly effective differentiating drugs all-trans retinoic acid and arsenic trioxide. Early trials showed a benefit of maintenance therapy on overall survival, although this benefit has been less clear in subsequent trials. This review assesses the differences in these trials and outlines a rational approach to maintenance therapy in APL, generally advising against maintenance in patients who underwent adequate consolidation therapy, particularly if they presented with low-risk disease (WBC < 10,000) and experienced molecular complete remission after completion of consolidation.     

Induction therapy in acute myeloid leukemia: Is it time to put aside standard 3 + 7?

For more than 30 years after its introduction, the combination of an anthracycline, usually daunorubicin, given for 3 days with continuous infusion of cytarabine for 7 days (3 + 7) has been the standard induction regimen for patients with acute myeloid leukemia (AML). In the last decade, there has been a progressive understanding of the molecular pathogenesis of the disease, which has led to discovery of potential therapeutic targets, resulting in selective treatment approaches aimed at rational and personalized treatment strategies. In the last 2 years, different new agents for AML have become widely available for newly diagnosed or relapsing/refractory patients, and others are object of clinical investigation. For most treatment‐naïve patients, it is now evident that standard 3 + 7 represents undertreatment in that the addition of new compounds results in better quality of response and improved survival. Hopefully, within few years, no patients with AML will be given standard 3 + 7 in the daily practice and a personalized approach targeting driving mutations will be widely applied.     

Myelodysplastic syndrome or acute myeloid leukemia? A study of 28 cases presenting with borderline features

Some patients present borderline features between acute myeloid leukemia (AML) and typical myelodysplastic syndromes (MDS): an excess of blasts insufficient to conclusively diagnose AML, yet above the figures usually compatible with MDS or the presence of Auer rods associated with a moderate excess of blasts. This presents considerable difficulties in diagnosis and management. The authors studied 28 such cases using the French-American-British Co-operative Group (FAB) classification, which groups them into a separate category termed "refractory anemia with excess of blasts in transformation" (RAEB-T). This was found to be a heterogenous group. Certain patients (4/28) had a previously established myelodysplasia, but most presented directly as RAEB-T. Two very different pictures emerged: a few patients (4/28) were young, with presentation and evolution similar to classic AML, for whom combination chemotherapy was effective; the majority (20/28) were older, with more varied clinical and cytologic presentation, for whom chemotherapy was of little effect and who presented a picture resembling classic RAEB with a median survival of 10 months.     

Are low-intensity induction strategies better for older patients with acute myeloid leukemia?

This study compares outcomes of low-intensity versus standard-intensity induction strategies for older patients with acute myeloid leukemia at the Weill Cornell Leukemia Program. From 1999 to 2009, 298 adults ≥ 60 years with AML underwent induction chemotherapy with low-intensity and standard-intensity regimens, based on physician and patient preferences and investigational protocol availability. Overall, 33% of the cohort achieved complete remission with initial treatment, 23% with low-intensity induction and 53% with standard-intensity induction (P<0.0001). The median overall survival was 6.5 months and there was no significant difference in overall survival between patients initially treated with a low-intensity regimen compared to those receiving standard-intensity induction. There were no differences in 30- or 60-day mortality between the two groups.     

Chronic myeloid leukemia in the tyrosine kinase inhibitor era: What is the best therapy?

Imatinib mesylate, 400 mg/d, is considered standard therapy for managing patients with chronic myeloid leukemia (CML) in chronic phase, yielding high rates of cytogenetic responses that translate into favorable long-term outcomes. However, some patients do not achieve adequate levels of response, lose a previously acquired response, or are forced to discontinue imatinib therapy because of safety reasons. To avoid these outcomes, several approaches are being tested in the frontline setting, including the use of higher imatinib doses or second-generation tyrosine kinase inhibitors such as nilotinib or dasatinib, the latter of which is approved only for managing patients who have imatinib therapy failure. Newer multikinase inhibitors active against multiple ABL1 mutations are also under development for patients in any CML phase who have therapy failure on sequential imatinib and a second-generation tyrosine kinase inhibitor or carry the highly resistant T315I mutation and are not candidates for allogeneic stem cell transplantation. Some of these approaches are expected to improve the outcomes of patients with CML.     

Prognostic impact of δ-like ligand 4 and Notch1 in acute myeloid leukemia

Notch signaling plays a critical role in embryonic vascular development and tumor angiogenesis. The present study was conducted to investigate the prognostic role of the angiogenesis-related Notch ligand and the receptor in acute myeloid leukemia (AML) and assess whether their expression correlates with that of the vascular endothelial growth factor (VEGF) and angiopoietin (Ang)-2. Bone marrow mononuclear cells from 60 untreated AML patients and 40 healthy controls were obtained. Real-time RT-PCR was performed to evaluate the mRNA expression of δ-like ligand 4 (Dll4), Notch1, VEGF, VEGF receptor (VEGFR)-1, VEGFR-2, Ang-1, Ang-2 and Tie2. Western blot analysis was used to determine the protein levels of Dll4 and Notch1. The results demonstrated that Dll4, Notch1, VEGF, VEGFR-2 and Ang-2 expression were significantly higher in untreated AML patients than in the controls. Univariate analysis of factors associated with the overall survival showed a significantly shorter survival in patients with the unfavorable karyotype, higher Dll4 expression, higher Notch1 expression, higher VEGF expression or higher Ang-2 expression. Furthermore, multivariate analysis revealed that the karyotype and expression levels of Notch1, Dll4, VEGF and Ang-2 were independent prognostic factors for overall survival. Additionally, the prognostic value of Dll4 expression (but not Notch1) was more significant in the subgroup consisting of patients with intermediate-risk cytogenetics. Subgroup analysis showed that Notch1 and Dll4 expression levels had a prognostic impact on patients with high VEGF or Ang-2 levels. Taken together, our data provide evidence that the activation of the Notch pathway may indicate an unfavorable prognosis in AML. In particular, Dll4 may be a relevant prognostic marker in intermediate-risk AML.     

Salvage chemotherapy regimens for acute myeloid leukemia: Is one better? Efficacy comparison between CLAG and MEC regimens

There is no standard salvage regimen for AML. We retrospectively compared two commonly used regimens at our institution: CLAG and MEC. The complete response rate (CR) was 37.9% for CLAG (n = 97) and 23.8% for MEC (n = 65) (P = 0.048), with median overall survival (OS) of 7.3 and 4.5 months, respectively (P = 0.05). In primary refractory disease, CR was 45.5% for CLAG and 22.2% for MEC (P = 0.09), with median OS of 11 and 4.5 months, respectively (P = 0.07). In first relapse, CR was 36.8% and 25.9% (P = 0.35) and median OS was 6.7 and 6.7 months, respectively (P = 0.87). Our data support use of CLAG for RR-AML.