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Reda Z Mahfouz,
Ania Jankowska,
Quteba Ebrahem,
Xiaorong Gu,
Valeria Visconte,
Ali Tabarroki,
Pramod Terse,
Joseph M Covey,
Kenneth K Chan,
Yonghua Ling,
Kory J Engelke, Mikkael Sekeres,
Ramon Tiu,
Jaroslaw P Maciejewski,
Tomas Radivoyevitch,
Yogen Saunthararajah
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ABSTRACT: PURPOSE: The cytidine analogues 5-azacytidine and decitabine, used to treat myelodysplastic syndromes (MDS), produce a molecular epigenetic effect, depletion of DNA-methyltransferase (DNMT1). This action is S-phase dependent. Hence, genetic factors that decrease the half-lives of these drugs could impact efficacy. Documentation of such impact, and elucidation of underlying mechanisms, could lead to improved clinical application. Design: Cytidine deaminase (CDA) rapidly inactivates 5-azacytidine/decitabine. The effect of CDA SNP A79C and gender on CDA expression, enzyme activity and drug pharmacokinetics/pharmacodynamics was examined in mice and humans, and the impact on overall survival (OS) was evaluated in 5-azacytidine/decitabine-treated MDS patients (n=90) and cytarabine-treated acute myeloid leukemia (AML) patients (n=76). RESULTS: By HPLC, plasma CDA activity was decreased as expected in individuals with the SNP A79C. Interestingly and significantly, there was an even larger decrease in females compared to males. Explaining this decrease, liver CDA expression was significantly lower in female versus male mice. As expected, decitabine plasma levels, measured by mass-spectrometry, were significantly higher in females. In mathematical modeling, the detrimental impact of shorter drug half-life (e.g., in males) was greater in low compared to high S-phase fraction disease (e.g., MDS versus AML), since in high S-phase fraction disease, even a short exposure treats a major portion of cells. Accordingly, in multivariate analysis, OS was significantly worse in male versus female MDS patients treated with 5-azacytidine/decitabine. CONCLUSIONS: Increased CDA expression/activity in males contributes to decreased cytidine analogue half-life and likely contributes to worse outcomes with 5-azacytidine or decitabine therapy.
Clinical Cancer Research 01/2013; · 7.74 Impact Factor
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Yogen Saunthararajah,
Pierre Triozzi,
Brian Rini,
Arun Singh,
Tomas Radivoyevitch, Mikkael Sekeres,
Anjali Advani,
Ramon Tiu,
Frederic Reu,
Matt Kalaycio,
Ed Copelan,
Eric Hsi,
Alan Lichtin,
Brian Bolwell
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ABSTRACT: Cytotoxic chemotherapy for acute myeloid leukemia (AML) usually produces only temporary remissions, at the cost of significant toxicity and risk for death. One fundamental reason for treatment failure is that it is designed to activate apoptosis genes (eg, TP53) that may be unavailable because of mutation or deletion. Unlike deletion of apoptosis genes, genes that mediate cell cycle exit by differentiation are present in myelodysplastic syndrome (MDS) and AML cells but are epigenetically repressed: MDS/AML cells express high levels of key lineage-specifying transcription factors. Mutations in these transcription factors (eg, CEBPA) or their cofactors (eg., RUNX1) affect transactivation function and produce epigenetic repression of late-differentiation genes that antagonize MYC. Importantly, this aberrant epigenetic repression can be redressed clinically by depleting DNA methyltransferase 1 (DNMT1, a central component of the epigenetic network that mediates transcription repression) using the deoxycytidine analogue decitabine at non-cytotoxic concentrations. The DNMT1 depletion is sufficient to trigger upregulation of late-differentiation genes and irreversible cell cycle exit by p53-independent differentiation mechanisms. Fortuitously, the same treatment maintains or increases self-renewal of normal hematopoietic stem cells, which do not express high levels of lineage-specifying transcription factors. The biological rationale for this approach to therapy appears to apply to cancers other than MDS/AML also. Decitabine or 5-azacytidine dose and schedule can be rationalized to emphasize this mechanism of action, as an alternative or complement to conventional apoptosis-based oncotherapy.
Seminars in Oncology 02/2012; 39(1):97-108. · 3.50 Impact Factor
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Anjali S Advani,
Sarah Gibson,
Elizabeth Douglas,
Julia Diacovo,
Paul Elson,
Matt Kalaycio,
Ed Copelan, Mikkael Sekeres,
Ronald Sobecks,
Shawnda Sungren,
Anand Lagoo,
David Rizzieri,
Eric Hsi
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ABSTRACT: Histone H4 acetylation was examined by immunohistochemistry in patients with acute lymphocytic leukaemia (ALL) in first relapse. Univariate and multivariate models identified correlates of complete remission (CR) and overall survival (OS). No variables were associated with achievement of CR. In multivariate analysis, weak histone H4 acetylation [Hazard Ratio (HR) 2·20, 95% confidence interval (CI) 0·93-5·23, P=0·07], shorter interval from diagnosis to relapse (<9 vs. 9-24 vs. >24 months) (HR 1·82, 95% CI 1·20-2·75, P= 0·005), and central nervous system involvement (HR 3·43, 95% CI 1·31-8·99, P=0·01) were independent poor prognostic factors for OS. These data provide a rationale for the use of histone deacetylase inhibitors in the treatment of relapsed ALL.
British Journal of Haematology 03/2011; 153(4):504-7. · 4.94 Impact Factor
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Anjali Advani,
Sarah Gibson,
Elizabeth Douglas,
Tao Jin,
Xiaoxian Zhao,
Matt Kalaycio,
Ed Copelan,
Ronald Sobecks, Mikkael Sekeres,
Shawnda Sungren,
Eric Hsi
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ABSTRACT: Abstract
Background
Histone deacetylase (HDAC) inhibitors are a novel anti-tumor therapy. To determine whether HDAC inhibitors may be useful in the treatment of adult acute lymphoblastic leukemia (ALL), we examined the acetylation of histone H4 by immunohistochemistry in newly diagnosed ALL patients and evaluated the impact of acetylation on complete remission (CR) rate, relapse-free survival (RFS), and overall survival (OS).
Methods
Patients ≥18 years of age and an available diagnostic bone marrow biopsy were evaluated. Cox proportional hazards analysis was used to identify univariate and multivariate correlates of CR, RFS, and OS. The variables histone H4 acetylation (positive or negative), white blood count, cytogenetic (CG) risk group (CALGB criteria), and age were used in multivariate analysis.
Results
On multivariate analysis, histone acetylation was associated with a trend towards an improved OS (for all CG risk groups) (HR = 0.51, p = 0.09). In patients without poor risk CG, there was an impressive association between the presence of histone acetylation and an improved CR rate (OR 3.43, p = 0.035), RFS (HR 0.07, p = 0.005), and OS (HR 0.24, p = 0.007). This association remained statistically significant in multivariate analysis.
Conclusions
These data provide a rationale for the design of novel regimens incorporating HDAC inhibitors in ALL.
BMC Cancer. 01/2010;
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Anjali S Advani,
Sarah E Gibson,
Elizabeth Douglas,
Tao Jin,
Xiaoxian Zhao,
Matt Kalaycio,
Ed Copelan,
Ronald Sobecks, Mikkael Sekeres,
Shawnda Sungren,
Eric D Hsi
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[hide abstract]
ABSTRACT: Histone deacetylase (HDAC) inhibitors are a novel anti-tumor therapy. To determine whether HDAC inhibitors may be useful in the treatment of adult acute lymphoblastic leukemia (ALL), we examined the acetylation of histone H4 by immunohistochemistry in newly diagnosed ALL patients and evaluated the impact of acetylation on complete remission (CR) rate, relapse-free survival (RFS), and overall survival (OS).
Patients > or = 18 years of age and an available diagnostic bone marrow biopsy were evaluated. Cox proportional hazards analysis was used to identify univariate and multivariate correlates of CR, RFS, and OS. The variables histone H4 acetylation (positive or negative), white blood count, cytogenetic (CG) risk group (CALGB criteria), and age were used in multivariate analysis.
On multivariate analysis, histone acetylation was associated with a trend towards an improved OS (for all CG risk groups) (HR = 0.51, p = 0.09). In patients without poor risk CG, there was an impressive association between the presence of histone acetylation and an improved CR rate (OR 3.43, p = 0.035), RFS (HR 0.07, p = 0.005), and OS (HR 0.24, p = 0.007). This association remained statistically significant in multivariate analysis.
These data provide a rationale for the design of novel regimens incorporating HDAC inhibitors in ALL.
BMC Cancer 01/2010; 10:387. · 3.01 Impact Factor
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ABSTRACT: The outcome of patients with acute lymphoblastic leukemia (ALL) in first relapse is poor. We retrospectively evaluated patients with ALL in first relapse, 18-60 years of age, to define a prognostic score. For all patients, a scoring system of 0-3 was developed with 1 point for each of the following: age at diagnosis >or=45 years, lactate dehydrogenase (LDH) at the time of relapse >or=1.5 times upper limits of normal (ULN), not proceeding to allogeneic bone marrow transplant (BMT). A similar scoring system was developed for patients proceeding to BMT. LDH >or=1.5 times ULN at the time of relapse predicted poor overall survival. Patients with a prognostic score of greater than 1 have a poor prognosis, even with BMT, and should be considered for treatment with innovative approaches such as Phase 1 clinical trials.
Leukemia & lymphoma 07/2009; 50(7):1126-31. · 2.40 Impact Factor
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ABSTRACT: Myelodysplastic syndromes (MDSs) are clonal hematologic disorders that frequently represent an intermediate disease stage before progression to acute myeloid leukemia (AML). As such, study of MDS/AML can provide insight into the mechanisms of neoplastic evolution. In 184 patients with MDS and AML, DNA methylation microarray and high-density single nucleotide polymorphism array (SNP-A) karyotyping were used to assess the relative contributions of aberrant DNA methylation and chromosomal deletions to tumor-suppressor gene (TSG) silencing during disease progression. Aberrant methylation was seen in every sample, on average affecting 91 of 1505 CpG loci in early MDS and 179 of 1505 loci after blast transformation (refractory anemia with excess blasts [RAEB]/AML). In contrast, chromosome aberrations were seen in 79% of early MDS samples and 90% of RAEB/AML samples, and were not as widely distributed over the genome. Analysis of the most frequently aberrantly methylated genes identified FZD9 as a candidate TSG on chromosome 7. In patients with chromosome deletion at the FZD9 locus, aberrant methylation of the remaining allele was associated with the poorest clinical outcome. These results indicate that aberrant methylation can cooperate with chromosome deletions to silence TSG. However, the ubiquity, extent, and correlation with disease progression suggest that aberrant DNA methylation is the dominant mechanism for TSG silencing and clonal variation in MDS evolution to AML.
Blood 11/2008; 113(6):1315-25. · 9.90 Impact Factor
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Anjali S Advani,
Tao Jin,
Giridharan Ramsingh,
Ramon Tiu,
Wael Saber,
Karl Theil,
Ronald Sobecks, Mikkael Sekeres,
Ed Copelan,
Shawnda Sungren,
Barbara Tripp,
Matt Kalaycio
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ABSTRACT: We evaluated patients with newly diagnosed ALL treated at the Cleveland Clinic during the years 1996 through 2005. Cox proportional hazards analysis was used to identify univariate and multivariate correlates of complete remission, overall survival and progression-free survival. On univariate analysis, significant prognostic factors included: age at diagnosis (per 10-year increase), poor risk cytogenetics, time to white blood count recovery, and time from induction chemotherapy (IC) to post-remission therapy (PRT). In patients age <60 years without poor risk cytogenetics, time from IC to PRT (per week increase) was a significant prognostic factor by multivariate analysis and was associated with a decreased progression-free survival [HR 1.27, CI (1.04-1.55), p = 0.019] and decreased overall survival [HR 1.34, CI (1.08-1.67), p = 0.009]. Delayed time from IC to PRT (> or =6.6 weeks) was associated with a statistically worse progression-free and overall survival.
Leukemia & lymphoma 08/2008; 49(8):1560-6. · 2.40 Impact Factor
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ABSTRACT: Cytogenetic analysis at the time of diagnosis predicts outcome in patients with acute myelogenous leukemia (AML). For those patients with favorable risk cytogenetics, stem cell transplant can be delayed until the time of relapse. For those patients with nonfavorable cytogenetic risk profiles, stem cell transplant may be required for optimal survival benefit. We treated patients with de novo AML and age less than 60 years first with etoposide, mitoxantrone, cytarabine, and G-CSF (EMA-G) to induce remission. Patients in complete remission were assigned to treatment with chemotherapy alone if they had favorable risk cytogenetics defined as the identification of a core-binding factor translocation. Patients with any other cytogenetic profile were assigned to treatment with either autologous or allogeneic stem cell transplant depending on the availability of an HLA-matched donor. Following EMA-G, 33 of 40 patients (83%) achieved CR. Of the 25 patients who actually were treated with postremission chemotherapy, 21 were treated with their assigned risk-adapted therapy. Of the 33 patients in remission, 5 year relapse-free survival (RFS) and overall survival (OS) was 46 and 38%, respectively. Our intensive and risk-adapted, stem cell transplant approach to the treatment of patients with AML requires a better definition of risk and does not appear to substantially improve results compared with more standard approaches.
American Journal of Hematology 08/2008; 83(11):831-4. · 4.67 Impact Factor
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Anjali S Advani,
Cristina Rodriguez,
Tao Jin,
Rony Abou Jawde,
Wael Saber,
Rachid Baz,
Matt Kalaycio,
Ronald Sobecks, Mikkael Sekeres,
Barbara Tripp,
Eric Hsi
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ABSTRACT: C-kit, a tyrosine kinase receptor, is expressed on most myeloid blasts and is thought to be important in the pathogenesis of AML. Activation of the c-kit receptor leads to phosphorylation and activation of downstream signaling proteins, which are important for cell survival and proliferation. Here, we discuss the prognostic impact of c-kit intensity, measured using the mean fluorescent index (MFI) in patients with newly diagnosed AML. On multivariate analysis, c-kit MFI>20.3 correlated with a decreased progression-free survival and overall survival, independent of known prognostic factors (age, white blood count at diagnosis and cytogenetics). Whether inhibiting c-kit in patients with AML will alter prognosis is the basis of ongoing clinical trials.
Leukemia Research 06/2008; 32(6):913-8. · 2.92 Impact Factor
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ABSTRACT: Standard practice in older patients with acute myeloid leukemia (AML) is induction chemotherapy (ICT) followed by post-remission chemotherapy (PRT). We previously reported a median disease-free survival (DFS) and overall survival (OS) for patients in complete remission (CR) of 7.5 and 13.5 months, respectively, in 30 older patients treated with standard ICT and PRT (study A). We designed a subsequent trial excluding PRT (study B). Forty patients with AML age > or =60 years were treated with ICT consisting of standard dose cytosine arabinoside and mitoxantrone followed with granulocyte-macrophage colony-stimulating factor subcutaneously starting day 11 if the bone marrow aspirate and biopsy was hypocellular. Median age was 68 years. Myelodysplasia preceded AML in 37% of patients. Favourable, normal, and unfavourable karyotypes were seen in 7.5%, 55%, and 37.5% of patients, respectively. Twenty-one patients (52.5%) achieved CR. Median DFS and OS for patients in CR were 6.2 and 10.8 months, respectively. Study A and B differed by the addition of PRT in study A. However, DFS and OS did not differ significantly between patients treated in study A or study B (P = 0.21 and P = 0.15, respectively). PRT has not clearly improved survival in older patients with AML, and therefore the routine addition of chemotherapy to older patients in complete remission is not indicated.
Leukemia and Lymphoma 05/2006; 47(4):689-95. · 2.58 Impact Factor
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ABSTRACT: Selecting the most appropriate treatment for patients with myelodysplastic syndromes (MDS) requires careful consideration of several factors. Most patients with MDS are in the 7th or later decade of life and often have comorbid health problems influencing treatment tolerance. Poor-prognosis MDS, as indicated by unfavorable cytogenetics or an increased percentage of myeloblasts, warrants more aggressive interventions than more indolent forms, which might remain stable for many years without treatment. The only curative treatment for MDS is allogeneic stem cell transplantation; however, only a small percentage of patients are candidates for this aggressive treatment. Traditional management for most patients with MDS is supportive care with red blood cell and platelet transfusions or hematopoietic growth factor support and antibiotics for infections. More detailed scrutiny of the processes involved in the MDS phenotype has stimulated investigation into identifying alternate therapeutic options that are effective and better tolerated. Herein, we summarize an array of novel treatments in development for the management of MDS.
Seminars in Hematology 08/2005; 42(3 Suppl 2):S32-7. · 3.99 Impact Factor
