Effects of azacitidine compared with conventional care regimens in elderly (≥75 years) patients with higher-risk myelodysplastic syndromes

Seymour, John F.; Fenaux, Pierre; Silverman, Lewis R.; Mufti, Ghulam J.; Hellström‐Lindberg, Eva; Santini, Valeria; List, Alan F.; Gore, Steven D.; Backstrom, Jay T.; McKenzie, David R.; Beach, C.L.

doi:10.1016/j.critrevonc.2010.04.005

Cited by 107 publications

(71 citation statements)

References 22 publications

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“…AZA is a DNA methyltransferase inhibitor that has been proven to be effective in high-risk MDS, because it can induce hematologic responses in 50-60% of cases, delay the AML evolution, and prolong the overall survival. 8,9,37,38 On the other hand, the clinical activity of HDAC inhibitors has also demonstrated a therapeutic potential as monotherapy, but above all in combination with a large number of conventional chemotherapeutic drugs, having a synergistic effect in enhancing their anticancer activity. 39,40 That is why several combination approaches based on HDAC inhibition and other novel drugs are being tested.…”

Section: Discussionmentioning

confidence: 99%

Synergistic induction of PI-PLCβ1 signaling by azacitidine and valproic acid in high-risk myelodysplastic syndromes

et al. 2010

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The association between azacitidine (AZA) and valproic acid (VPA) has shown high response rates in high-risk myelodysplastic syndromes (MDS) cases with unfavorable prognosis. However, little is known about the molecular mechanisms underlying this therapy, and molecular markers useful to monitor the disease and the effect of the treatment are needed. Phosphoinositide-phospholipase C (PI-PLC) b1 is involved in both genetic and epigenetic mechanisms of MDS progression to acute myeloid leukemia. Indeed, AZA as a single agent was able to induce PI-PLCb1 expression, therefore providing a promising new tool in the evaluation of response to demethylating therapies. In this study, we assessed the efficacy of the combination of AZA and VPA on inducing PI-PLCb1 expression in high-risk MDS patients. Furthermore, we observed an increase in Cyclin D3 expression, a downstream target of PI-PLCb1 signaling, therefore suggesting a potential combined activity of AZA and VPA in high-risk MDS in activating PI-PLCb1 signaling, thus affecting cell proliferation and differentiation. Taken together, our findings might open up new lines of investigations aiming at evaluating the role of the activation of PI-PLCb1 signaling in the epigenetic therapy, which may also lead to the identification of innovative targets for the epigenetic therapy of high-risk MDS.

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Section: Discussionmentioning

confidence: 99%

Synergistic induction of PI-PLCβ1 signaling by azacitidine and valproic acid in high-risk myelodysplastic syndromes

et al. 2010

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“…Importantly, the study of azacitidine has revealed nuances of treatment with DNMTi therapy not seen with the use of traditional chemotherapy. These include improved OS, which can occur in the absence of a complete remission (CR),7, 8, 22 a need to treat with as many as 6 treatment cycles prior to achieving maximal response, and hematologic toxicities seen during early treatment tend to decrease if patients can remain on treatment 7, 8, 23…”

Section: Introductionmentioning

confidence: 99%

Extended dosing with CC‐486 (oral azacitidine) in patients with myeloid malignancies

Savona

Kolibaba²,

Conkling

et al. 2018

American J Hematol

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CC‐486 (oral azacitidine) is an epigenetic modifier in clinical development for treatment of hematological cancers. This study of extended CC‐486 dosing included patients with myelodysplastic syndromes (MDSs), chronic myelomonocytic leukemia (CMML), or acute myeloid leukemia (AML). After a pharmacokinetic assessment period, 31 patients (MDS n = 18, CMML n = 4, and AML n = 9) entered a clinical phase in which they received CC‐486 300 mg once‐daily for 21 days of repeated 28‐day cycles. Median age was 71 years (range: 53‐93); 42% of patients were aged ≥75 years. A total of 5 patients with AML (63%) had prior MDS. Median number of CC‐486 treatment cycles was 4 (range: 1‐32). The most common treatment‐emergent adverse events (TEAEs) were gastrointestinal (84% of patients) and hematologic (81%). Most common grade 3‐4 TEAEs were neutropenia (n = 13, 42%) and anemia (n = 9, 29%). Ten patients experienced grade 4 neutropenia. Infrequently, CC‐486 dose was interrupted or reduced due to gastrointestinal (n = 5, 16%) or hematologic (n = 6, 19%) TEAEs. Overall response rate (complete remission [CR], CR with incomplete hematological recovery [CRi], partial remission [PR], marrow CR) in the MDS/CMML subgroups was 32% and in the AML subgroup (CR/CRi/PR) was 22%. Red blood cell transfusion independence rates in the MDS/CMML and AML subgroups were 33% and 25%, respectively, and 2 MDS/CMML patients attained hematologic improvement as a best response on‐study. No baseline gene mutation was predictive of response/nonresponse. CC‐486 allows flexible dosing and schedules to improve tolerability or response. Neutropenia in early treatment cycles deserves scrutiny and may warrant initiation of prophylactic antibiotics.KEY POINTSThe safety profile of oral CC‐486 was comparable to that of injectable azacitidine; most adverse events were hematological and gastrointestinal.Extended (21‐day/cycle) CC‐486 dosing induced responses in patients with hematological malignancies, many of whom had prior DNMTi failure.

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“…In particular, the risk of infection is elevated among high-risk MDS patients who often present with neutropenia [2][3][4]. Neutrophil count may further decrease following hypomethylation agents therapy [5,6] which has become the standard of care for these patients.…”

Section: Introductionmentioning

confidence: 99%

Predicting infections in high‐risk patients with myelodysplastic syndrome/acute myeloid leukemia treated with azacitidine: Aretrospective multicenter study

et al. 2013

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Hypomethylating agents have become the standard therapy for patients with high‐risk myelodysplastic syndrome (MDS). In Israel, azacitidine (AZA) is routinely used. Yet, infectious complications are common during AZA therapy. The current study was aimed to evaluate the incidence and predisposing risk factors for infections in AZA‐treated patients. This retrospective study included patients treated with AZA in 18 Israeli medical institutions between 2008 and 2011. Data on 184 patients [157 high‐risk MDS and 27 acute myeloid leukemia (AML)], with a median age of 71.6 (range 29–92) were recorded. Overall, 153 infectious events were reported during 928 treatment cycles (16.5%) administered to 100 patients. One hundred fourteen, 114/153 (75%) events required hospitalization and 30 (19.6%) were fatal. In a univariate analysis, unfavorable cytogenetics, low neutrophil, hemoglobin (Hb) and platelet (PLT) counts were found to be associated with infections (24.4% vs. 12.9%, P < 0.0001; 27% vs. 13.5%, P < 0.0001; 20.4% vs. 11%, P < 0.0001 and 29.2% vs. 14.2%, P < 0.0001, respectively). In multivariate analysis, only low Hb level, low PLT count, and unfavorable cytogenetics remained significant. Prior to therapy, poor cytogenetics, PLT count below 20 × 109/L and neutrophil count below 0.5 × 109/L were predictive of the risk of infection during the first two cycles of therapy. In conclusion, patients with unfavorable cytogenetics, presenting with low neutrophil and PLT counts, are susceptible to infections. Evaluation of infection risk should be repeated prior to each cycle. Patients with poor cytogenetics in whom AZA is prescribed despite low PLT count are particularly at high risk for infections and infection prophylaxis may be considered. Am. J. Hematol. 88:130–134, 2013. © 2012 Wiley Periodicals, Inc.

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Effects of azacitidine compared with conventional care regimens in elderly (≥75 years) patients with higher-risk myelodysplastic syndromes

Cited by 107 publications

References 22 publications

Synergistic induction of PI-PLCβ1 signaling by azacitidine and valproic acid in high-risk myelodysplastic syndromes

Synergistic induction of PI-PLCβ1 signaling by azacitidine and valproic acid in high-risk myelodysplastic syndromes

Extended dosing with CC‐486 (oral azacitidine) in patients with myeloid malignancies

Predicting infections in high‐risk patients with myelodysplastic syndrome/acute myeloid leukemia treated with azacitidine: Aretrospective multicenter study

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