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Summary: This study compared decitabine exposure when administered IV (DEC‐IV) at a dose of 20 mg/m2 for 5‐days with orally administered decitabine with cedazuridine (DEC‐C), as well as the clinical efficacy and safety of DEC‐C in patients with acute myeloid leukaemia (AML) who were ineligible for intensive induction chemotherapy. In all, 89 patients were randomised 1:1 to DEC‐IV or oral DEC‐C (days 1–5 in a 28‐day treatment cycle), followed by 5 days of the other formulation in the next treatment cycle. All patients received oral DEC‐C for subsequent treatment cycles until treatment discontinuation. Equivalent systemic decitabine exposures were demonstrated (5‐day area under the curve ratio between the two decitabine formulations of 99.64 [90% confidence interval 91.23%, 108.80%]). Demethylation rates also were similar (≤1.1% difference). Median overall survival (OS), clinical response and safety profile with oral DEC‐C were consistent with those previously observed with DEC‐IV. Next‐generation sequencing was performed to identify molecular abnormalities that impact OS and TP53 mutations were associated with a poor outcome. These findings support the use of oral DEC‐C in patients with AML. [ABSTRACT FROM AUTHOR]

A study published in the journal Hematological Oncology examined the prescription patterns of venetoclax (VEN) in patients with newly diagnosed acute myeloid leukemia (AML) who are unfit for intensive chemotherapy. The study found that in real-world practice, the average daily dose of VEN was lower than the recommended dose, and most patients experienced multiple dose reductions and interruptions during treatment. Patients who received lower dosages of VEN had higher mortality rates in the following months. The study suggests that further research is needed to evaluate the effect of changes in the dosing schedule on patient outcomes and to identify predictors of sub-optimal adherence to therapy. [Extracted from the article]

Simple Summary: The association of venetoclax (VEN) with hypomethylating agents (HMAs) such as azacitidine (AZA) and decitabine (DECI) significantly improved the outcome of patients with newly diagnosed acute myeloid leukemia (AML) who are not eligible for intensive chemotherapy. However, it is not clear how applicable the results of clinical trials are in a real-world setting. For this reason, we conducted a systematic review and meta-analysis of real-world studies on this type of AML patient. Overall, AML patients treated with VEN+HMAs had a lower survival rate than was reported in the pivotal VIALE-A trial. Results slightly increased when the analysis was restricted to the studies using VEN+AZA as treatment. Future studies are warranted to investigate whether this discrepancy is due to the different characteristics of enrolled patients or to a non-optimal adherence to therapy. In recent years, the association of venetoclax (VEN) with hypomethylating agents (HMAs) significantly improved the outcome of patients with newly diagnosed acute myeloid leukemia (AML) who were unfit for intensive chemotherapy and became the standard of care after the publication of the pivotal RCT VIALE-A. However, it is still not clear to what extent the results observed in the VIALE-A apply to a real-world setting. For this reason, we carried out a systematic review and meta-analysis of real-world studies on newly diagnosed patients with AML, ineligible for intensive induction chemotherapy, receiving first-line VEN+HMA. We then compared their results in term of survival with those from the VIALE-A. Kaplan-Meier curves were extracted from all included studies and individual survival data was reconstructed. We then estimated a pooled survival curve and compared it with the results of the VIALE-A using the log-rank test. We also conducted a secondary analysis including only studies considering VEN plus azacytidine (AZA) as treatment, as this was the schedule originally used in the VIALE-A. Nineteen real-world studies met the inclusion criteria and were included in the systematic review. Most of them reported a worse survival than the VIALE-A. The pooled survival curve was similar to that reported in the VIALE-A during the first three months of treatment but diverged thereafter (p-value = 0.0001). The pooled median survival among the real-world studies was 9.37 months (95%CI 8.81–10.5), substantially lower than that reported in the VIALE-A (14.7 months; 95%CI 11.9–18.7). Results slightly increased when the analysis was restricted to the studies using VEN+AZA as treatment (median survival: 11.5 months; 95%CI 10.2–14.8). Survival of newly diagnosed AML patients treated with VEN+HMAs in a real-world setting seems to be lower than previously reported in the VIALE-A, while the effect of VEN+AZA is more in line with expected results. Future studies are needed to evaluate whether this apparent discrepancy is due to the different characteristics of enrolled patients or to a non-optimal adherence to therapy, and whether alternative regimens can provide better results in terms of safety and effectiveness. [ABSTRACT FROM AUTHOR]

Diacylglycerol kinases (DGKs) play dual roles in cell transformation and immunosurveillance. According to cancer expression databases, acute myeloid leukemia (AML) exhibits significant overexpression of multiple DGK isoforms, including DGKA, DGKD and DGKG, without a precise correlation with specific AML subtypes. In the TGCA database, high DGKA expression negatively correlates with survival, while high DGKG expression is associated with a more favorable prognosis. DGKA and DGKG also feature different patterns of co-expressed genes. Conversely, the BeatAML and TARGET databases show that high DGKH expression is correlated with shorter survival. To assess the suitability of DGKs as therapeutic targets, we treated HL-60 and HEL cells with DGK inhibitors and compared cell growth and survival with those of untransformed lymphocytes. We observed a specific sensitivity to R59022 and R59949, two poorly selective inhibitors, which promoted cytotoxicity and cell accumulation in the S phase in both cell lines. Conversely, the DGKA-specific inhibitors CU-3 and AMB639752 showed poor efficacy. These findings underscore the pivotal and isoform-specific involvement of DGKs in AML, offering a promising pathway for the identification of potential therapeutic targets. Notably, the DGKA and DGKH isoforms emerge as relevant players in AML pathogenesis, albeit DGKA inhibition alone seems insufficient to impair AML cell viability. [ABSTRACT FROM AUTHOR]

BACKGROUND: The efficacy of azacitidine for the treatment of high-risk myelodysplastic syndromes has prompted the issue of its potential role even in the treatment of acute myeloid leukemia (AML). METHODS: The authors analyzed 82 patients with AML who were diagnosed according to World Health Organization criteria. The median patient age was 72 years (range, 29-87 years), and 27 patients (33%) had secondary AML. Of 62 patients with evaluable cytogenetics, 18 patients (29%) had a poor-risk karyotype, and 44 patients (71%) had an intermediate karyotype. Thirty-five patients (43%) received azacitidine as front-line treatment, and 47 patients (57%) had previously received 1 or more line of chemotherapy. RESULTS: The overall response rate was 32% (26 of 82 patients) and included 12 (15%) complete remissions (CRs), 4 (5%) CRs with incomplete blood count recovery (CRi), and 10 (12%) partial responses (PRs). Responses were observed more frequently among untreated patients compared with pretreated patients; in fact, 17 of 35 untreated patients (48%) responded, including 11 responses (31%) classified as CR/CRi. Conversely, only 9 of 47 pretreated patients (19%) responded, including 5 responses (11%) that were classified as CR/Cri. The response rate was significantly higher for untreated patients ( P = .006) and those who had white blood cell counts <10 × 109/L ( P = .006). For untreated patients who achieved a response, the median overall response duration was 13 months, and the 1-year and 2-years overall survival rates were 58% and 24%, respectively. CONCLUSIONS: The current results indicated that azacitidine promises to be an effective therapy for elderly patients with untreated AML and with white blood cell counts <10 × 109/L. Cancer 2012;. © 2011 American Cancer Society. [ABSTRACT FROM AUTHOR]

We analyzed by immunocytochemistry the expression of survivin in bone marrow cells from 36 acute myeloid leukemia (AML) cases, from 98 patients with myelodysplastic syndrome (MDS), and from 41 non hemopathic subjects. Our aim was to evaluate whether abnormalites in survivin expression were associated with peculiar laboratory and clinical findings, altered apoptosis levels or altered proliferative rate. In normal samples survivin was never detectable. It was detected in almost all AML and MDS cases. In AML and in MDS with more than 5% bone marrow blasts survivin levels higher than in RA and RARS were observed ( P  = 0.04). In MDS a tendential inverse correlation between survivin and TUNEL positivity was identified ( P  = 0.08), whereas survivin expression was independent of the proliferative rate. Survivin levels did not predict disease progression in MDS; among AML patients treated with intensive polichemotherapy, survivin expression was significantly higher in resistant cases ( P  = 0.01). Our findings confirm the high incidence of survivin expression in AML. Its abnormal expression also in MDS may play a role in promoting aberrantly increased cell viability and contribute to the altered homeostatic balance between cell growth and cell death. [ABSTRACT FROM AUTHOR]

Background: Acute myeloid leukemia is a heterogeneous hematological disease, characterized by karyotypic and molecular alterations. Mutations in IDH2 have a role in diagnosis and as a minimal residue disease marker. Often the variant allele frequency during follow up is less than 20%, which represents the limit of detection of Sanger sequencing. Therefore, the development of sensitive methodologies to identify IDH2 mutations might help to monitor patients' response to therapy. We compared three different methods to identify and monitor IDH2 mutations in patients' specimens. Methods: Performances of PNA-PCR clamping, droplet digital PCR and Sanger for IDH2 status identification were evaluated and compared in 96 DNA patients' specimens. Results: In contrast with Sanger sequencing, our results highlighted the concordance between PNA clamping and digital PCR. Furthermore, PNA-PCR clamping was able to detect more mutated DNA with respect to Sanger sequencing that showed several false negatives independently from the allelic frequency. Conclusions: We found that PNA-PCR clamping and digital PCR identified IDH2 mutations in DNA samples with comparable results in a percentage significantly higher compared to Sanger sequencing. PNA-PCR clamping can be used even in laboratories not equipped for sophisticated analyses, decreasing cost and time for IDH2 characterization. [ABSTRACT FROM AUTHOR]