- [Show abstract] [Hide abstract] ABSTRACT: Introduction: Therapeutic strategies in patients with acute myeloid leukemia (AML) have not changed significantly over the last decades. Appropriate strategies are ultimately driven by the assessment of patients’ fitness to define suitability for intensive induction chemotherapy, which produces high initial remission rates but, increased likelihood of relapse. Old/unfit AML patients still represent an urgent and unmet therapeutic need. Epigenetic deregulation represents a strategic characteristic of AML pathophysiology whereby aberrant gene transcription provides an advantage to leukemic cell survival. Efforts to re-establish impaired epigenetic regulation include hypomethylating agents and histone deacetylase inhibitors (HDACi). Areas covered: The review discusses the underlying mechanisms leading to disruption of lysine acetyltransferases (KAT or HAT)/deacetylase (KDAC or HDAC) balance and the rationale for using the HDACi panobinostat (LBH-589) in AML. Expert opinion: Although panobinostat has produced significant results in myeloma, its efficacy remains limited in AML. Panobinostat exerts pleiotropic activity and lack of specificity, which likely contributes to its inadequate safety in elderly AML patients. Phase I-II trials, utilizing panobinostat associated with well-known chemotherapeutic agents are ongoing and combinations with other druggable targets may likely be evaluated in future trials. The clinical use of this HDACi in AML the near future does not appearing promising.
- [Show abstract] [Hide abstract] ABSTRACT: Purpose: The initial results of the APL0406 trial showed that the combination of all-trans-retinoic acid (ATRA) and arsenic trioxide (ATO) is at least not inferior to standard ATRA and chemotherapy (CHT) in first-line therapy of low- or intermediate-risk acute promyelocytic leukemia (APL). We herein report the final analysis on the complete series of patients enrolled onto this trial. Patients and methods: The APL0406 study was a prospective, randomized, multicenter, open-label, phase III noninferiority trial. Eligible patients were adults between 18 and 71 years of age with newly diagnosed, low- or intermediate-risk APL (WBC at diagnosis ≤ 10 × 10(9)/L). Overall, 276 patients were randomly assigned to receive ATRA-ATO or ATRA-CHT between October 2007 and January 2013. Results: Of 263 patients evaluable for response to induction, 127 (100%) of 127 patients and 132 (97%) of 136 patients achieved complete remission (CR) in the ATRA-ATO and ATRA-CHT arms, respectively (P = .12). After a median follow-up of 40.6 months, the event-free survival, cumulative incidence of relapse, and overall survival at 50 months for patients in the ATRA-ATO versus ATRA-CHT arms were 97.3% v 80%, 1.9% v 13.9%, and 99.2% v 92.6%, respectively (P < .001, P = .0013, and P = .0073, respectively). Postinduction events included two relapses and one death in CR in the ATRA-ATO arm and two instances of molecular resistance after third consolidation, 15 relapses, and five deaths in CR in the ATRA-CHT arm. Two patients in the ATRA-CHT arm developed a therapy-related myeloid neoplasm. Conclusion: These results show that the advantages of ATRA-ATO over ATRA-CHT increase over time and that there is significantly greater and more sustained antileukemic efficacy of ATO-ATRA compared with ATRA-CHT in low- and intermediate-risk APL.
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- [Show abstract] [Hide abstract] ABSTRACT: Chronic lymphocytic leukemia (CLL) is characterized by extremely variable clinical course indicating substantial differences in the biology of the disease. Molecular characterization provides new insights useful for treatment decision making. We report on a patient diagnosed with CLL, whose disease was characterized by episodes of rapid progression and disease stabilization, and in which a SRSF2 gene mutation was identified in the absence of other commonly known mutations of CLL. To the best of our knowledge this is the first case of SRSF2 gene mutation ever reported in CLL.
- [Show abstract] [Hide abstract] ABSTRACT: The APL0406 study showed that arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) is not inferior to standard ATRA and chemotherapy (CHT) in newly diagnosed, low-intermediate risk acute promyelocytic leukemia (APL). We analysed the kinetics of PML-RARα transcripts by RQ-PCR in bone marrow samples from 184 patients and assessed the prognostic impact of fms-related tyrosine kinase 3 internal tandem duplication (FLT3-ITD) in 159 patients enrolled in this trial in Italy. After induction therapy, the reduction of PML-RARα transcripts was significantly greater in patients receiving ATRA-CHT compared to those treated with ATRA-ATO (3.4 vs 2.9 logs; P=0.0182). Conversely, at the end of consolidation a greater log-reduction of PML-RARα transcripts was detected in the ATRA-ATO compared to the ATRA-CHT group (6.3 vs 5.3 logs; P=0.0024). FLT3-ITD mutations had no significant impact on either event-free survival (EFS) or cumulative incidence of relapse (CIR) in patients receiving ATRA-ATO, while a trend for inferior EFS was observed in FLT3-ITD-positive patients receiving ATRA-CHT. Our study shows at the molecular level that ATRA-ATO exerts at least equal and probably superior anti-leukemic efficacy compared to ATRA-CHT in low-intermediate risk APL. The data also suggest that ATRA-ATO may abrogate the negative prognostic impact of FLT3-ITD.Leukemia accepted article preview online, 02 May 2016. doi:10.1038/leu.2016.122.
- [Show abstract] [Hide abstract] ABSTRACT: The management of Acute Promyelocytic Leukemia (APL) has considerably evolved during the past two decades. The advent of All-trans retinoic acid (ATRA) and its inclusion in combinatorial regimens with anthracycline chemotherapy has provided cure rates exceeding 80%; however this widely adopted approach also conveys significant toxicity including severe myelosuppression and rare occurrence of secondary leukemias. More recently, the advent of arsenic trioxide (ATO) and its use in association with ATRA with or without chemotherapy has further improved patient outcome by allowing to minimize the intensity of chemotherapy thus reducing serious toxicity while maintaining high anti-leukemic efficacy. The advantage of ATRA-ATO over ATRA-chemotherapy has been recently demonstrated in two large randomized trials and this option has now become the new standard of care in low-risk (i.e. non-hyperleucocytic) patients. In light of its rarity, abrupt onset and high risk of early death and due to specific treatment requirements, APremains a challenging condition which needs to be managed in highly experienced centers. We review here the results of large clinical studies conducted in newly diagnosed APL as well as the recommendations for appropriate diagnosis, prevention and management of the main complications associated to modern treatment of the disease.
- [Show abstract] [Hide abstract] ABSTRACT: Background Recent studies indicate that angiogenesis is important in the pathogenesis of acute myeloid leukemias (AMLs). Among the various AMLs, the bone marrow angiogenetic response is particularly pronounced in acute promyelocytic leukemia (APL). However, the molecular mechanisms responsible for this angiogenetic response are largely unknown. In the present study, we have explored the role of HHEX, a homeodomain transcription factor, as a possible mediator of the pro-angiogenetic response observed in APL. This transcription factor seems to represent an ideal candidate for this biologic function because it is targeted by PML-RARα, is capable of interaction with PML and PML-RARα, and acts as a regulator of the angiogenetic response. Methods We used various cellular systems of APL, including primary APL cells and leukemic cells engineered to express PML-RARα, to explore the role of the PML-RARα fusion protein on HHEX expression. Molecular and biochemical techniques have been used to investigate the mechanisms through which PML-RARα downmodulates HHEX and the functional consequences of this downmodulation at the level of the expression of various angiogenetic genes, cell proliferation and differentiation. Results Our results show that HHEX expression is clearly downmodulated in APL and that this effect is directly mediated by a repressive targeting of the HHEX gene promoter by PML-RARα. Studies carried out in primary APL cells and in a cell line model of APL with inducible PML-RARα expression directly support the view that this fusion protein through HHEX downmodulation stimulates the expression of various genes involved in angiogenesis and inhibits cell differentiation. Conclusions Our data suggest that HHEX downmodulation by PML-RARα is a key event during APL pathogenesis. Electronic supplementary material The online version of this article (doi:10.1186/s13045-016-0262-5) contains supplementary material, which is available to authorized users.
- [Show abstract] [Hide abstract] ABSTRACT: Patients with acute promyelocytic leukemia who received all-trans retinoic acid (ATRA) plus arsenic trioxide had an event-free survival rate of 96% at 50 months and an overall survival rate of 99%, better results than with ATRA plus chemotherapy (81% and 88%, respectively).
- [Show abstract] [Hide abstract] ABSTRACT: Chromosomal translocations encode oncogenic fusion proteins that have been proven to be causally involved in tumorigenesis. Our understanding of whether such genomic alterations also affect non-coding RNAs is limited, and their impact on circular RNAs (circRNAs) has not been explored. Here, we show that well-established cancer-associated chromosomal translocations give rise to fusion circRNAs (f-circRNA) that are produced from transcribed exons of distinct genes affected by the translocations. F-circRNAs contribute to cellular transformation, promote cell viability and resistance upon therapy, and have tumor-promoting properties in in vivo models. Our work expands the current knowledge regarding molecular mechanisms involved in cancer onset and progression, with potential diagnostic and therapeutic implications.
- [Show abstract] [Hide abstract] ABSTRACT: All trans retinoic acid (ATRA) has revolutionized the therapy of acute promyelocytic leukemia (APL). Treatment of this leukemia with ATRA in combination with chemotherapy has resulted in complete remission rates >90 % and long-term remission rates above 80 %. Furthermore, the combination of ATRA and arsenic trioxide (ATO) was shown to be safe and effective in frontline treatment and, for patients with low and intermediate risk disease, possibly superior to the standard ATRA and anthracycline-based regimen. However, in spite of this tremendous progress, APL still remains associated with a high incidence of early death due to the frequent occurrence of an abrupt bleeding diathesis. This hemorrhagic syndrome more frequently develops in high-risk APL patients, currently defined as those exhibiting >10 × 10(9)/L WBC at presentation. In addition to high WBC count, other molecular and immunophenotypic features have been associated with high-risk APL. Among them, the expression in APL blasts of the stem/progenitor cell antigen CD34, the neural adhesion molecule (CD56), and the T cell antigen CD2 help to identify a subset of patients at higher risk of relapse and often the expression of these markers is associated with high WBC count. At the molecular level, the short PML/RARA isoform and FLT3-internal tandem duplication (ITD) mutations have been associated with increased relapse risk. These observations indicate that extended immunophenotypic and molecular characterization of APL at diagnosis including evaluation of CD2, CD56, and CD34 antigens and of FLT3 mutations may help to better design risk-adapted treatment in this disease.
- [Show abstract] [Hide abstract] ABSTRACT: Acute promyelocytic leukaemia (APL) is characterized by the PML/RARA fusion transcript. PML and RARA mutations have been shown to directly respond to arsenic trioxide (ATO) and all-trans retinoic (ATRA). We analysed the prevalence of PML mutations in 32 patients with de novo or therapy-related APL (t-APL; n = 5), treated with ATO. We identified one ATO-resistant t-APL patient, who presented a PML A216T mutation in both the rearranged and unrearranged PML alleles, and two mutations in the rearranged RARA gene. In this patient, subclones with different PML and RARA mutations acquired clonal dominance during the disease course, probably leading to treatment resistance.
- [Show abstract] [Hide abstract] ABSTRACT: The outcome of patients with acute promyelocytic leukaemia (APL) has dramatically improved over the last two decades, due to the introduction of combined all-trans retinoic acid (ATRA) and chemotherapy regimens and, more recently, to the advent of arsenic trioxide (ATO). ATRA and anthracycline-based chemotherapy remains a widely used strategy, providing cure rates above 80%, but it is associated with risk of severe infections and occurrence of secondary leukaemias. ATO is the most effective single agent in APL and, used alone or in combination with ATRA or ATRA and reduced-intensity chemotherapy, results in greater efficacy with considerably less haematological toxicity. The toxic profile of ATO includes frequent, but manageable, QTc prolongation and increase of liver enzymes. Two large randomized studies have shown that ATRA + ATO is superior to ATRA + chemotherapy for newly diagnosed low-risk APL resulting in 2-4 year event-free survival rates above 90% and very few relapses. According to real world data, the spectacular progress in APL outcomes reported in clinical trials has not been paralleled by a significant improvement in early death rates, this remains the most challenging issue for the final cure of the disease.
- [Show abstract] [Hide abstract] ABSTRACT: The TP73 gene transcript is alternatively spliced and translated into the transcriptionally active (TAp73) or inactive (ΔNp73) isoforms, with opposite effects on the expression of TP53 target genes and on apoptosis induction. The imbalance between ΔNp73 and TAp73 may contribute to tumorigenesis and resistance to chemotherapy in human cancers, including hematological malignancies. In acute promyelocytic leukemia (APL), both isoforms are expressed, but their relevance in determining response to therapy and contribution to leukemogenesis remains unknown. Here, we provide the first evidence that a higher ΔNp73/TAp73 RNA expression ratio is associated with lower survival, lower disease-free survival, and higher risk of relapse in patients with APL homogeneously treated with all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy, according to International Consortium on Acute Promyelocytic Leukemia (IC-APL) study. Cox proportional hazards modeling showed that a high ΔNp73/TAp73 ratio was independently associated with shorter overall survival (hazard ratio: 4.47, 95% confidence interval: 1.64-12.2; P=0.0035). Our data support the hypothesis that the ΔNp73/TAp73 ratio is an important determinant of clinical response in APL and may offer a therapeutic target for enhancing chemosensitivity in blast cells.
- [Show abstract] [Hide abstract] ABSTRACT: Purpose of review: This review will discuss issues arising along with the expanding use of hypomethylating treatment (HMT) in the management of acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS). Recent findings: HMT has been shown to induce responses in MDS and AML, and azacitidine (Vidaza, Celgene) has been shown to prolong survival in higher-risk MDS. Recent studies have supported the idea that disease stability may also be a treatment goal, whereas treatment interruption in responding patients is associated with rapid disease relapse and death. In AML, a modest but significant survival advantage has been shown for HMT by censoring patients at the time of subsequent AML therapy, but the major limitation remains the short duration of responses. Unfortunately, some of the strategies to overcome these limitations have failed, including the combination of HMT to histone-deacetylase inhibitors, which has not definitively shown to significantly prolong survival. Molecules interfering with other pathways impacting the survival and proliferation of blasts, used alone or in combination, including guadecitabine, selinexor, or inhibitors of IDH2 mutations, are more promising approaches. Summary: Hypomethylating drugs are the first successful treatment for elderly patients with higher-risk MDS and are effective for some AML subtypes. Translational studies will hopefully identify patients with a favorable profile of response to these drugs, and help to identify newer targets for combination treatments.