Hematologic improvement and response in elderly AML/RAEB patients treated with valproic acid and low-dose Ara-C

Corsetti, Maria Teresa; Salvi, Flavia; Perticone, Sonia; Baraldi, Anna; Paoli, Lorella De; Gatto, Simona; Pietrasanta, Daniela; Pini, Massimo; Primon, Valeria; Zallio, Francesco; Tonso, Anna; Alvaro, MT Garcia de; Ciravegna, G; Levis, Alessandro

doi:10.1016/j.leukres.2011.02.021

Cited by 43 publications

(31 citation statements)

References 37 publications

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“…Novel approaches, such as clofarabine, lenalidomide, hypomethylating agents and low-dose cytarabine combined with valproic acid are, therefore, being actively studied as alternatives. [37][38][39][40] We conducted a phase II trial of low-dose DAC in this population. Despite accumulated poor-risk patient features, the objective response rate was 26%, and an additional 26% of patients achieved an antileukemic effect.…”

Section: Discussionmentioning

confidence: 99%

A multicenter phase II trial of decitabine as first-line treatment for older patients with acute myeloid leukemia judged unfit for induction chemotherapy

Lübbert¹,

Rüter²,

Claus³

et al. 2011

Haematologica

210

161

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The online version of this article has a Supplementary Appendix. BackgroundThe treatment of acute myeloid leukemia of older, medically non-fit patients still poses a highly unmet clinical need, and only few large, prospective studies have been performed in this setting. Given the established activity of hypomethylating agents such as 5-aza-2'-deoxycytidine (decitabine) in myelodysplastic syndromes and acute myeloid leukemia with 20-30% bone marrow blasts, we investigated whether this drug is also active in patients with more than 30% blasts. Design and MethodsTo evaluate the efficacy and toxicity of decitabine in patients over 60 years old with untreated acute myeloid leukemia ineligible for induction chemotherapy, 227 patients (median age, 72 years), many with comorbidities, adverse cytogenetics and/or preceding myelodysplastic syndrome were treated with this hypomethylating agent. During the initial decitabine treatment (135 mg/m 2 total dose infused intravenously over 72 hours every 6 weeks), a median of two cycles was administered (range, 1-4). All-trans retinoic acid was administered to 100 patients during course 2. Fifty-two patients who completed four cycles of treatment subsequently received a median of five maintenance courses (range, 1-19) with a lower dose of decitabine (20 mg/m 2 ) infused over 1 hour on 3 consecutive days every 4-6 weeks. ResultsThe complete and partial remission rate was 26%, 95% CI (20%, 32%), and an antileukemic effect was noted in 26% of patients. Response rates did not differ between patients with or without adverse cytogenetics; patients with monosomal karyotypes also responded. The median overall survival from the start of decitabine treatment was 5.5 months (range, 0-57.5+) and the 1-year survival rate was 28%, 95%CI (22%,34%). Toxicities were predominantly hematologic. ConclusionsDecitabine is well tolerated by older, medically non-fit patients with acute myeloid leukemia; myelosuppression is the major toxicity. The response rate and overall survival were not adversely influenced by poor-risk cytogenetics or myelodysplastic syndrome. Because of these encouraging results, randomized studies evaluating single-agent decitabine versus conventional treatment are warranted. The study is registered with the German Clinical Trials Registry, number DRKS00000069. chemotherapy. Haematologica 2012;97(3):393-401. doi:10.3324/haematol.2011 This is an open-access paper.A multicenter phase II trial of decitabine as first-line treatment for older patients with acute myeloid leukemia judged unfit for induction chemotherapy

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Section: Discussionmentioning

confidence: 99%

A multicenter phase II trial of decitabine as first-line treatment for older patients with acute myeloid leukemia judged unfit for induction chemotherapy

Lübbert¹,

Rüter²,

Claus³

et al. 2011

Haematologica

210

161

View full text Add to dashboard Cite

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“…Sodium valproate was added as an HDAC inhibitor in view of the upcoming data in AML patients and especially in view of high-risk cytogenetic features in our patient. [39,40] Both valproic acid as well as 6TG have been shown to have antiangiogenic activity. [41,42] The antiangiogenic activity of 6TG, together with its antimetabolite activity toward tumor cells, may contribute to its action during maintenance therapy in AML.…”

Section: Discussionmentioning

confidence: 99%

Is there a role for metronomic induction (and maintenance) therapy in elderly patients with acute myeloid leukemia? A literature review

et al. 2013

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Acute myeloid leukemia (AML) in older adults differs biologically and clinically from that in younger patients and is characterized by adverse chromosomal abnormalities, stronger intrinsic resistance, and lower tolerance to chemotherapy. In patients over age 60 with AML, cure rates are under 10% despite intensive chemotherapy, and most of them die within a year of diagnosis. Over the last decade, metronomic chemotherapy has emerged as a potential strategy to control advanced/refractory cancer. Here, we report a case of a 68-year-old gentleman having AML with high-risk cytogenetic features, who achieved complete remission on our oral metronomic PrET (PrET: Prednisolone, etoposide, thioguanine) protocol on an outpatient basis. He was later treated with standard high-dose (HD) cytosine arabinoside (Ara-C) consolidation followed by maintenance with etoposide, thioguanine, and sodium valproate. Presently, the patient is nearly 35 months since diagnosis and 21 months off treatment. This case report and review highlights that the combination of oral low-intensity metronomic therapy, followed by standard HD consolidation therapy and metronomic maintenance therapy may be well tolerated by elderly patients especially with less proliferative, high (cytogenetic)-risk AML who are otherwise deemed to be unfit for intensive intravenous induction chemotherapy regimens. References for this review were identified through searches of Pubmed for recent publications on the subject as well as searches of the files of the authors themselves. The final list was generated on the basis of originality and relevance to this review.

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“…61% had resistant or relapsed disease suggesting VPA might restore sensitivity to cytarabine [118]. However, the second study in 15 patients of a similar cohort found no clinical responses and concluded limited clinical activity [119].…”

Section: Aliphatic Acidsmentioning

confidence: 99%

Histone deacetylase inhibitors: recent outcomes from clinical trials and the implications for oncology treatment approaches

Marsh¹,

Narramore²,

Chapple³

et al. 2013

Clinical Investigation

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Histone deacetylases play an important role in multiple processes, including gene expression, proliferation, apoptosis, cytoskeletal organization, migration and angiogenesis. Histone deacetylase inhibitors are able to induce cell death and growth arrest as targeted anticancer agents. Whilst only two, vorinostat and romidepsin, are licensed in oncology, several have reached Phase III trials and many more are in Phase I and II. In addition to this, multiple novel drugs, including more targeted agents, are emerging from preclinical studies. This paper examines the outcomes of recent clinical trials in 11 key histone deacetylase inhibitors, both as monotherapy and in combination with other antitumor drugs. An overview of the advantages and disadvantages between the different classes and individual drugs is discussed, as well as a brief outlook on the future developments in the field.

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Hematologic improvement and response in elderly AML/RAEB patients treated with valproic acid and low-dose Ara-C

Cited by 43 publications

References 37 publications

A multicenter phase II trial of decitabine as first-line treatment for older patients with acute myeloid leukemia judged unfit for induction chemotherapy

A multicenter phase II trial of decitabine as first-line treatment for older patients with acute myeloid leukemia judged unfit for induction chemotherapy

Is there a role for metronomic induction (and maintenance) therapy in elderly patients with acute myeloid leukemia? A literature review

Histone deacetylase inhibitors: recent outcomes from clinical trials and the implications for oncology treatment approaches

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