Treatment of therapy related acute promyelocytic leukemia with the combination of all trans retinoic acid and arsenic trioxide without chemotherapy: a series of three patients.

Departments of Internal Medicine.
Leukemia & lymphoma (Impact Factor: 2.61). 03/2010; 51(5):933-6. DOI: 10.3109/10428191003697484
Source: PubMed
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    ABSTRACT: Therapy-related acute myeloid leukemia (t-AML) is occasionally associated with favorable risk cytogenetics including core binding factor AML and acute promyelocytic leukemia (APL). It is unclear if these leukemias have the same favorable outcomes as their de novo counterparts. Interpretation of published data is difficult due to lack of data on the contribution of the original neoplasm as well as its treatment to overall mortality. Based on available evidence, we conclude that t-AML with favorable risk cytogenetics have superior outcomes among t-AMLs and should be treated similar to de novo AML in patients who are candidates for definitive therapy. Therapy-related APL has similar outcome as de novo APL. There is no evidence at the present time to support the routine use of allogeneic HSCT in first complete remission in t-AML with favorable cytogenetics.
    Leukemia research 09/2012; · 2.36 Impact Factor
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    ABSTRACT: Treatment for a pre-existing condition using chemotherapy, radiation therapy, immunosuppressive therapy, or a combination of these modalities may lead to the devastating complication of therapy-related myelodysplastic syndrome or acute myeloid leukemia (t-MDS/t-AML), collectively known as therapy-related myeloid neoplasm (t-MN). This disorder arises as a direct consequence of mutational events induced by the primary treatment. The outcomes for these patients have been historically poor compared to people who develop AML de novo. Currently comprising 10-20% of all cases of AML, t-MN is relatively resistant to conventional leukemia therapies, and is associated with s ort survival times. Median life expectancy from diagnosis is about 8-10 months in most series. Although the spectrum of cytogenetic abnormalities in t-AML is similar to AML de novo, the frequency of unfavorable cytogenetics, such as a complex karyotype or deletion or loss of chromosomes 5 and/or 7, is considerably higher in t-MN. Two distinct groups of patients with t-MN have been described. The more common subtype, seen in about 75% of patients, typically occurs 5-7 years after first exposure to alkylating agents or radiation, is often preceded by a myelodysplastic syndrome (MDS), and is frequently accompanied by clonal cytogenetic abnormalities such as the loss of all or part of chromosomes 5 or 7. Mutations of the P53 tumor suppressor gene are also common. The risk is related to total cumulative exposure over time to alkylating agents. In contrast, among individuals who develop t-AML after treatment with topoisomerase II inhibitors, the latency period to the development of t-AML is often only 1-3 years, antecedent MDS is rare, and gene rearrangements involving MLL at 11q23 or RUNX1/AML1 at 21q22 are common. It is now well recognized that APL and other subtypes of AML with balanced translocations sometimes occur as therapy-related myeloid neoplasms (t-MN) in patients who have previously received cytotoxic therapy or ionizing radiation therapy (RT). The most of this review will focus on these "good risk" leukemias, i.e. those with APL or inv(16)/t(16;16) or t(8;21).
    Mediterranean Journal of Hematology and Infectious Diseases 01/2011; 3(1):e2011032.
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    ABSTRACT: A112 is a tamibarotene dimethylaminoethyl ester considered a candidate compound for the treatment of acute promyelocytic leukemia (APL) and acute myeloid leukemia (AML). Our goal in this study was to evaluate the efficacy of anti-cancer activity, beginning by studying its inhibitory effects on leukemia cells and then comparing it to tamibarotene. A112 effectively inhibited the growth of HL-60 and NB4 cells as estimated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The inhibitory effect of A112 was confirmed in mice in which A112 delayed the growth of HL-60 xenografts after 3 weeks' injection. The efficacy of A112 on leukemia cell growth was stronger than that of tamibarotene at the same dosage. The detection of A112 and tamibarotene in plasma of rats showed that A112 might sustain release of its hydrolysate tamibarotene, and the concentration was maintained at a higher level and for a longer time than that of tamibarotene injection. We studied the differentiation morphologies of leukemic cells exposed to A112 or tamibarotene. The number of differentiated NB4 cells was increased, suggesting that A112 possessed differentiation activity in the inhibition of leukemia growth. Further studies showed that the expression of CD11b, a marker of terminal granulocyte differentiation, was increased as estimated by flow cytometry with a direct immunofluorescence assay. A112 was found to induce the activation of CCAAT/enhancer-binding protein β (C/EBPβ) and cyclin-dependent kinase (CDK) inhibitors p21(Waf1/cip1) and p27(Kip1) while cell growth was inhibited. These activities of A112 were greater than those of tamibarotene. The higher efficacy of A112 was also evidenced by induction of apoptosis in leukemia cells. A112 induced a greater number of annexin V-positive cells than did tamibarotene as measured by flow cytometry analysis. Treatment of mice with A112 resulted in stronger terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining in HL-60 xenografts. Western blot analysis revealed that A112 increased the expression of caspase-3, caspase-9 and cleaved poly(ADP-ribose) polymerase (PARP) in leukemia cells both in vitro and in vivo, indicating that induction of apoptosis was involved in the inhibition of leukemia growth. Taken together, these results suggest that A112 is a highly effective derivative of trans retinoic acid and a potential candidate compound for the treatment of leukemia.
    Leukemia & lymphoma 08/2011; 53(2):295-304. · 2.61 Impact Factor