Survival Benefit with Decitabine Compared to Historical Experience with Intensive Chemotherapy in Patients with Higher Risk Myelodysplastic Syndrome (MDS).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2652-2652
Author(s):  
Elias Jabbour ◽  
Hagop M. Kantarjian ◽  
Jorge Cortes ◽  
William G. Wierda ◽  
Alessandra Ferrajoli ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Survival Benefit ◽  
Chromosomal Abnormalities ◽  
Independent Effect ◽  
Poor Performance Status ◽  
Study Group ◽  
Intensive Chemotherapy ◽  
Historical Experience ◽  
Group A ◽  
Group B

Abstract Background Decitabine is a hypomethylating agent, approved by the FDA for treating MDS. Intensive chemotherapy is one treatment option in higher risk MDS. The comparative efficacy of these two strategies, decitabine vs. intensive chemotherapy, has not been evaluated. Study Aims Compare the results of decitabine in MDS with contemporary historical experience with intensive chemotherapy (as used in AML) in patients with higher risk MDS. Study Group and Treatment The study group treated with decitabine included 115 patients with higher risk MDS treated on our decitabine frontline study. (Kantarjian, Blood 2006; First Edition Online). The contemporary historical experience included two cohorts: Group A: 115 patients receiving intensive chemotherapy from 1995–2005 and matched for age, IPSS and cytogenetics; and Group B: All 376 patients treated with intensive chemotherapy from 1995–2005 with similar entry criteria as the decitabine study. Patients received decitabine 20 mg/m2 IV/D x 5 every four weeks. Response was evaluated by the modified IWG criteria (Cheson, Blood 108:419, 2006) In comparing decitabine to Group B, a multivariate analysis was conducted to assess the independent effect of decitabine vs. intensive chemotherapy. Results 115 patients were treated with decitabine; median age 64 years (range 37–89 years). IPSS risk groups: intermediate-1 17%, intermediate-2 30%, high 15%, not assessable 39%. Decitabine was given for a median of 7 courses (range 1 to 23); number of decitabine courses 3 or more in 81/89 patients (91%) followed on study for at least 6 months. Hemoglobin <10 g/dL in 76%; thrombocytopenia <100 x 109/L in 72%; ANC <1.0 x 109/L in 47%; chromosomal abnormalities in 63%; prior therapy for MDS in 54%; marrow blast 5% or more in 79%. Overall, 80 patients (70%) achieved IWG response: CR 40 (35%), PR 2 (2%), marrow CR +/− other hematologic improvements (HI) 26 (23%), other HI 12 (10%). Median remission duration was 20 months; median survival was 21 months. The CR rates by AML criteria (Cheson JCO21:4642, 2003) were 43% with decitabine and 46% with intensive chemotherapy in Group A, and 52% with intensive chemotherapy in Group B. Mortality at 6 weeks was 3% with decitabine vs. 12% with intensive chemotherapy (p=0.002); the 3-month mortality was 7% with decitabine vs. 22% with intensive chemotherapy. The survival was better with decitabine versus intensive chemotherapy in Group A (median 22 month vs. 11 month; estimated 2-year survival rate 47% vs. 25%, p<0.001). A multivariate analysis for survival in all 491 patients receiving decitabine or intensive chemotherapy (Group B) identified the following to be independent adverse factors for survival: abnormal cytogenetics, older age, anemia, thrombocytopenia, and poor performance status. Entering decitabine vs. intensive chemotherapy after accounting for the effect of other prognostic factors selected decitabine as an independent favorable prognostic factor for survival (pvalue 0.002; hazard risk 0.76). Conclusions Compared with intensive chemotherapy decitabine is associated with a survival benefit in higher risk MDS.

scholarly journals The Significance and Optimal Number of Cycles of HD-AraC Consolidation Chemotherapy for Non-CBF AML

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2298-2298
Author(s):  
Yosuke Nagahata ◽  
Yoshimitsu Shimomura ◽  
Yotaro Ochi ◽  
Yusuke Koba ◽  
Yasuhiro Kazuma ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Survival Benefit ◽  
Univariate Analysis ◽  
Hazard Ratio ◽  
High Dose ◽  
Consolidation Chemotherapy ◽  
Group A ◽  
Number Of Cycles ◽  
Group B ◽  
Intermediate Dose

Abstract Background: High-dose cytarabine (HD-AraC) is a promising therapy for acute myeloid leukemia (AML). However, it causes substantial toxicity, such as severe cytopenia and cytarabine-encephalopathy. The efficacy of HD-AraC for the treatment of core-binding-factor (CBF) AML has been well established; however, whether or not HD-AraC is suitable for the treatment of non-CBF AML is unclear. Moreover, it remains controversial whether HD-AraC is effective before allogeneic hematopoietic stem cell transplantation (allo-HSCT) for the treatment of non-CBF AML. In this study, we investigated the efficacy of HD-AraC in terms of optimal numbers of HD-AraC cycles required to treat non-CBF AML patients who did and did not receive allo-HSCT. Methods: We retrospectively collected the data of consecutive AML patients who were aged 15-70 years, treated in our hospital and diagnosed between Jan. 2000 and Apr. 2014. Patients with acute promyelocytic leukemia (APL) and CBF AML were excluded. Only patients who achieved complete remission (CR) and received post-remission therapies with a curative intent were included; namely, only those who received allo-HSCT or completed more than one cycle of consolidation chemotherapy. Patients who exclusively received azacytidine-based or low-dose AraC-based therapies were excluded. HD-AraC therapy was defined as a chemotherapeutic regimen utilizing 12 g/m2/cycle or more of AraC. Patients who were not suitable for HD-AraC because of comorbidities were also excluded. Overall survival (OS) was separately analyzed in patients who underwent allo-HSCT in the 1st CR (group A) and in those who did not (group B). The unadjusted probabilities of OS were estimated using the Kaplan-Meier method, and univariate analysis was done using the log-rank test. Multivariate analysis was performed with Cox proportional hazard regression models, and 95% confidence intervals (CIs) were calculated. In multivariate analysis, the number of cycles of HD-AraC, age, cytogenetic data, and whether or not the patient achieved CR after the 1st cycle of chemotherapy were used as covariates. In group A, donor source and conditioning were also considered as covariates. Results: A total of 166 non-APL, non-CBF AML patients were identified. Seventy-one patients were excluded for the following reasons: 50 did not achieve CR, 13 underwent incomplete consolidation therapies because of complications or early relapse, 7 had missing data, and 1 had chronic renal disease. For HD-AraC, toxicity was not a consideration for the discontinuation of treatment, but the dose of AraC was reduced to an intermediate dose (AraC<12g/m2/cycle) in some patients if severe toxicity was encountered. Among the 95 patients included in the study, the median age was 51 years. Twelve patients had unfavorable cytogenetics, and 50 patients received allo-HSCT in the 1st CR and were assigned to group A. As the treatment policy for consolidation therapy has undergone substantial changes in the last 15 years and the dose of AraC was switched from a high dose to an intermediate dose in some patients, the number of cycles of HD-AraC used for consolidation varied. The three-year OS (3y-OS) of patients who received 0, 1, 2, or >2 cycles of HD-AraC were 50.6%, 85.7%, 75.0%, and 68.6% (n=22, 9, 8, 11) in group A, and 44.3%, 16.0%, 65.6%, and 50.0% (n=19, 10, 10, 6) in group B, respectively. Univariate analysis showed that patients in group A who received one or more cycles of HD-AraC had a longer 3y-OS (75.4% vs 50.6%, p=0.024) (figure 1), whereas patients in group B who received two or more cycles of HD-AraC had a longer 3y-OS (57.1% vs 36.2%, p=0.078) (figure 2). Multivariate analysis of patients in group A showed that one or more cycles of HD-AraC resulted in a survival benefit (Hazard ratio=0.26, 95%CI: 0.070-0.98, p=0.046), whereas multivariate analysis of patients in group B showed that two or more cycles of HD-AraC (Hazard ratio=0.36, 95%CI: 0.13-0.97, p=0.044) and intermediate-risk of cytogenetics resulted in a survival benefit. Conclusion: For consolidation chemotherapy, at least one cycle of HD-AraC is recommended for patients who plan to receive allo-HSCT, and at least two cycles is required for other patients. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

Does laryngopharyngeal reflux affect healing and recovery after tonsillectomy?

2007 ◽  
Vol 122 (6) ◽  
pp. 603-608 ◽  
Author(s):  
S Elwany ◽  
Y A Nour ◽  
E A Magdy
Keyword(s):  
Wound Healing ◽  
Laryngopharyngeal Reflux ◽  
Ph Monitoring ◽  
Control Group ◽  
Study Group ◽  
Pain Scores ◽  
Blinded Study ◽  
Group A ◽  
Group B ◽  
Control Group Group

AbstractIntroduction:Laryngopharyngeal reflux is increasingly being implicated in several otolaryngological disorders.Aims:To study a potential correlation between pre-operative laryngopharyngeal reflux and wound healing and recovery after tonsillectomy, based on subjective and objective findings.Materials and methods:A prospective, blinded study was undertaken, including 60 patients scheduled for tonsillectomy, divided into two equal groups: a study group (group A) with pre-operative laryngopharyngeal reflux documented using ambulatory 24-hour pH monitoring; and a control group (group B) without laryngopharyngeal reflux.Results:Group A had significantly higher pain scores on the seventh and 14th post-operative days (p = 0.022 and p = 0.000, respectively) and took a significantly longer time to return to normal eating (p = 0.013), compared with group B. Group A also showed significantly slower healing on the seventh and 14th post-operative days, as estimated by assessing the grade of post-operative slough formation (p = 0.016 and p = 0.029, respectively). A significant correlation between the number of pharyngeal reflux episodes and the degree of post-operative slough was also found.Conclusions:Laryngopharyngeal reflux can significantly decrease wound healing following tonsillectomy. Therefore, pre-operative recognition and management of this condition is desirable in order to eliminate its negative post-operative effect.

Comparison of Post-Operative Quality of Life between Vaginal Hysterectomy and Abdominal Hysterectomy

2021 ◽  
Vol 15 (7) ◽  
pp. 1801-1803
Author(s):  
Nazia Sajjad ◽  
Sara Qadir ◽  
Rukhsana Kasi ◽  
Tayyaba Rasheed ◽  
Fozia Unar ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Vaginal Hysterectomy ◽  
Controlled Trial ◽  
Abdominal Hysterectomy ◽  
Study Group ◽  
Randomized Controlled ◽  
Group A ◽  
Group B ◽  
Satisfactory Quality

Objectives: To compare the frequency of satisfactory quality of life between vaginal hysterectomy and abdominal hysterectomy. Study Design: Randomized controlled trial. Place and Duration of Study: Department of Obstetrics and Gynecology, Niazi Medical & Dental College, Sargodha from 1st April 2020 to 31st December 2020. Methodology: Ninety patients were comprised and they were divided in two groups; group A (vaginal hysterectomy) and Group B (abdominal hysterectomy) were performed. Hysterectomies (vaginal or abdominal) were performed by consultant gynecologist having experience at having least 5 years). Results: Mean age of the patients was 49.82±3.207 years, mean age of the patients of group A was 49.82±3.193 years and mean age of the patients of group B was 49.82±3.256 years. Satisfactory quality of life was noted in 38 (84.44%) patients of study group A and 29 (64.44%) patients of study group B. Statistically significant (P = 0.051) difference between the frequency of satisfactory quality of life between the both groups was noted. Conclusion: Results of this study reveals that post hysterectomy quality of life found more satisfactory in vaginal hysterectomy group as compared to abdominal hysterectomy group. Insignificant association of post hysterectomy quality of life with age group, marital status, parity and socio-economical status was found. Findings of this study also revealed that post hysterectomy satisfactory quality of life is not associated with education of the patients. Key words: Hysterectomy, Quality of life, abdomen, vagina, WHO, Uterus

scholarly journals Can Co-enzyme Q10 improve the chances of conception after the age of 35?

2017 ◽  
Vol 6 (7) ◽  
pp. 2729
Author(s):  
Eman Ali Abd El Fattah
Keyword(s):  
Chromosomal Abnormalities ◽  
Normal Pregnancy ◽  
Metabolic Energy ◽  
Secondary Outcome ◽  
Slowing Down ◽  
Ovulation Stimulation ◽  
Before And After ◽  
History Of ◽  
Group A ◽  
Group B

Background: ovarian follicular quality diminishes with age, Free radicals and oxidative stress begin to accumulate in cells, aging or slowing down the metabolic energy production centers in the cell- the mitochondria. When the mitochondria cannot generate a certain amount of energy, it slows growth and proper development of the follicle making it more prone to DNA damage, including chromosomal abnormalities resulting in poor fertilization patterns, and early miscarriage. Co-enzyme Q10 (CoQ10) is a major cellular antioxidant. its tissue levels gradually decrease with age. We attempt to evaluate its protective effect on ROS-induced ovarian damage, which is one of the most important and widely accepted patho- mechanisms underlying cell ageing.Methods: 40 Participants   from El Shatby hospital infertility clinic 35 to 38 years old, with history of bad response to ovulation stimulation, were divided into two equal groups (group A given (CoQ10) 3mg|kg body weight for three cycles prior to stimulation Serum anti- mullarian hormone level was measured before and after CoQ10 administration, group B= twenty cases as control). Participants were given gonadotrophins (150 IU to 375 IU). Follicular growth was monitored by trans- vaginal ultra- sonography and serum estradiol level (E2). Ovulation trigger was achieved using 10,000 IU of human chorionic gonadotrophin.Results: The primary outcome was occurrence of normal pregnancy; secondary outcome was good response to stimulation (at least one mature follicle 18-22mm).Conclusions: CoQ10 has no significant effect on response to ovulation stimulation or on pregnancy rates.

scholarly journals Comparison of Different Diagnostic Method for Mycobacteria Tuberculosis in Suspected Patients

1970 ◽  
Vol 7 (2) ◽  
pp. 84-88
Author(s):  
AR Khagi ◽  
S Singh ◽  
S Subba ◽  
A Bajracharya ◽  
R Tuladhar ◽  
...  
Keyword(s):  
Comparative Study ◽  
Sputum Smear ◽  
Study Group ◽  
Bacterial Cells ◽  
X Ray ◽  
Smear Examination ◽  
Group A ◽  
Chest X Ray ◽  
Group B ◽  
Sputum Smear Examination

Background: Microbial examination of smear of AFB by Z-N stain is currently the most rapid method for the detection of M. tuberculosis but its sensitivity is low i.e. required at least 10,000 bacterial cells per ml of sputum and also none specific, but auramine staining method has higher sensitivity than that of the Z-N stain but there are chances of false positive. Objective of this study was to find the correlation between chest X-ray, direct sputum smear examination by Ziehl-Neelsen stain, Auramine fluorochrome stain and sputum culture for M. tuberculosis. Methods: During that study period 250 x 3 samples were taken three each from 250 patients and divided into two groups A and B by performing Auramine fluorochrome stain in all samples . In group A, there were 150 fluorochrome stain positive samples. One each from 150 patient for comparative study of direct sputum smear examination by Ziehl-Neelsen stain, , culture on LJ medium and chest X-ray. Similarly in group B, next 100 fluorochrome stain negative specimens one each from 100 patients were taken for the comparative study of direct sputum smear examination by Ziehl-Neelsen stain, culture and chest X-ray. Results: In the study group A (n=150) all the specimens were positive in Auramine fluorochrome stain and all of them show positive in X-ray but only 134 showed positive in Ziehl-Neelsen stain and 136 showed positive in culture. In the study group B (n=100), all the specimens were negative in Auramine fluorochrome stain and all of them show negative in Ziehl-Neelsen stain but 14 of them were positive in culture and 24 were positive in chest X-ray. Conclusions: The diagnosis of PTB could be made by Auramine fluorochrome microscopy and culture. Key words: auramine fluorochrome stain; culture; mycobacterium tuberculosis; x-ray; ziehl-neelsen. DOI: 10.3126/jnhrc.v7i2.3012 Journal of Nepal Health Research Council Vol.7(2) Apr 2009 84-88

SUBLINGUAL MISOPROSTOL FOR PREVENTION OF POSTPARTUM HAEMORRHAGE – A RANDOMISED CONTROL TRIAL

2021 ◽  
pp. 56-57
Author(s):  
Anupama Anupama
Keyword(s):  
Caesarean Section ◽  
Blood Loss ◽  
Outcome Measures ◽  
Post Partum ◽  
Randomised Control Trial ◽  
Study Group ◽  
Sublingual Misoprostol ◽  
Group A ◽  
Post Partum Haemorrhage ◽  
Group B

Aim – The aim of the study was to study the effect of sublingual misoprostol for prevention of PPH. Materials and Methods – This was a prospective, randomized, double blind, placebo controlled study. Inclusion criteria were women aged 20-40 years with 38-40 weeks of gestation who underwent elective caesarean section. Exclusion criteria were women have risk factors for post-partum haemorrhage, active thromboembolic disease and intrinsic risk for thrombosis. Participants were randomly assigned to misoprostol group or group A (n=50) and placebo group or group B(n=50). Group A received 400µg of sublingual misoprostol after delivery of the baby, group B received placebo tablet at the same time. Primary outcome measures were blood loss from delivery of the placenta to the end of the caesarean section to 2 hours postpartum, haemoglobin estimation was done in all patients pre operatively and 24 hours post operatively and the change in concentration was noted. Secondary outcome measures were need for additional uterotonics, use of additional surgical interventions to control post-partum haemorrhage. Result – Blood loss from both placental delivery to the end of caesarean section and from end of caesarean section to 2 hours postpartum were signicantly lower in the study group. (p<0.0001). Change ifn haemoglobin concentration in study group was also signicantly less than in the control group. (p<0.0001). Total amount of Oxytocin required was signicantly less in the study group (p=0.01). The number of women requiring other oxytocics (inj. Methyl ergometrine, inj. Carboprost) was signicantly less in study group (p=0.0078). Conclusion – Sublingual misoprostol has been found to be effective in preventing PPH.

Dose-intensive cyclophosphamide with etoposide and vincristine for pediatric solid tumors: a phase I/II pilot study by the Australia and New Zealand Childhood Cancer Study Group.

1994 ◽  
Vol 12 (3) ◽  
pp. 522-531 ◽  
Author(s):  
L White ◽  
G McCowage ◽  
G Kannourakis ◽  
V Nayanar ◽  
L Colnan ◽  
...  
Keyword(s):  
New Zealand ◽  
Pilot Study ◽  
Childhood Cancer ◽  
Solid Tumors ◽  
Hematologic Toxicity ◽  
Study Group ◽  
Cancer Study ◽  
Cancer Study Group ◽  
Group A ◽  
Group B

PURPOSE This pilot study of the Australia and New Zealand Childhood Cancer Study Group investigated the effectiveness and toxicity of a regimen incorporating vincristine (VCR), etoposide, and divided-dose, escalating cyclophosphamide (CPA) (VETOPEC) in 23 patients aged 1 to 20 years with solid tumors. PATIENTS AND METHODS Seventeen patients (group A) had recurrent or refractory tumors after prior multiagent therapy, and six patients (group B) with adverse prognostic indicators were treated at initial presentation. Treatment cycles were 21 to 28 days and consisted of vincristine (0.05 mg/kg) on days 1 and 14, with etoposide (2.5 mg/kg/d) plus escalating CPA on days 1, 2, and 3. The CPA dosage was escalated from 30 mg/kg/d in cycle no. 1 by 5 mg/kg/d in each cycle to a maximum of 55 mg/kg/d in cycle no. 6. RESULTS Of 20 patients assessable for tumor response, 19 (95%) responded after two to six cycles of VETOPEC: seven complete responses (CRs); eight very good partial responses (VGPRs); and four partial responses (PRs). In group A, 13 of 14 (93%) assessable patients responded (five CRs, four VGPRs, four PRs), and in group B, five stage IV and one stage III patient achieved two CRs and four VGPRs. The principal toxicity was myelosuppression. Grade IV neutropenia occurred after 98% of cycles, and the incidence of grade IV thrombocytopenia increased from 37% after cycle no. 1 to 91% after cycle no. 6 (P = .002). A total of 115 cycles delivered were followed by 62 febrile admissions (54%), and showed a significant rise with increasing cycles (P = .001). One patient died of septicemia. CONCLUSION This combination and scheduling produced a high response rate in patients with recurrent, refractory, or advanced solid tumors of childhood. Further studies of this regimen and of strategies to reduce hematologic toxicity are warranted.

scholarly journals Histological studies on the retina and cerebellum of Wistar rats treated with Arteether™

2014 ◽  
Vol 31 (01) ◽  
pp. 028-032
Author(s):  
A. Okunlola ◽  
C. Okunlola ◽  
C. Okani ◽  
O. Adewole ◽  
D. Ofusori ◽  
...  
Keyword(s):  
Wistar Rats ◽  
Study Group ◽  
Group A ◽  
Cervical Dislocation ◽  
Nissl Stain ◽  
Group B ◽  
Haematoxylin And Eosin Stain ◽  
Therapeutic Doses ◽  
Cellular Components ◽  
Group D

Abstract Introduction: Arteether™, a derivative of artemisinin, is among the recent drugs that have given renewed hope for combating malarial menace. The present study investigated the effects of arteether™ on the histology of the retina and cerebellum of Wistar rats. Materials and Methods: Twenty adult albino Wistar rats weighing 150-200 g, were randomly divided into four groups (A, B, C and D) of five animals each and used for this study. Group A rats were given intramuscular (i.m.) arteether™ (3 mg/kg b.w.) daily for 3 days. Group B rats were given i.m. arteether™ (6 mg/kg b.w.) daily for 3 days. Group C rats were also given i. m. of arteether™ (3 mg/kg b. w.) daily for 3 days, and the same dose was repeated at two-weekly intervals for 4 further weeks; while Group D rats which received normal saline (0.9 % w/v, 3 ml/kg b.w.), served as controls. At the end of the experiment, the rats were sacrificed by cervical dislocation. The retina and cerebellum were excised and processed routinely for histopathology changes, using haematoxylin and eosin stain (H & E), as well as Nissl stain. Results: Results obtained showed normal cellular components of the retina and cerebellum in all groups, and no cyto-pathological changes were observed. Conclusion: Thus, this study showed that under light microscopic examination, therapeutic doses of arteether™ caused no significant cyto-pathologic changes in the retina and cerebellum of Wistar rats.

The influence of clinical and laboratory factors on the formation of monopronucleated zygotes after intracytoplasmic sperm injection (ICSI)

Zygote ◽  
2019 ◽  
Vol 27 (02) ◽  
pp. 64-68 ◽  
Author(s):  
Gemma Fabozzi ◽  
Emilia Rega ◽  
Maria Flavia Starita ◽  
Maria Giulia Amendola ◽  
Antonio Colicchia ◽  
...  
Keyword(s):  
Study Group ◽  
Stimulation Protocol ◽  
Female Age ◽  
Duration Of Therapy ◽  
Polar Bodies ◽  
Group A ◽  
Laboratory Variables ◽  
Male Patients ◽  
Group B ◽  
Estradiol Levels

SummaryThe aim of the present study was to determine whether clinical or laboratory factors can influence the development of single pronucleated zygotes (1PN) and two polar bodies (PB) after ICSI. In total, 341 ICSI cycles performed at FertiClinic-Villa Margherita from January 2012 to December 2014 were enrolled in the study. Group A included 240 cycles with no 1PN−2PB while group B included 101 cycles with one or more 1PN−2PB. Age, stimulation protocol, infertility factor, amount of gonadotropin administered, duration of therapy, peak estradiol levels, number of follicles at maturation triggering, oocytes retrieved and mature oocytes, time between retrieval and injection and sperm characteristics were compared between groups. In opposition to previous results showing no relationship between 1PN occurrence and clinical or laboratory variables, we observed that 1PN−2PB zygote formation seems to be associated with a lower female age, higher level of E2 and higher number of follicles on day of oocyte maturation triggering, higher number of astenozoospermic male patients, more oocytes retrieved at pick-up, more mature oocytes (MII) and longer time to injection.

The Histone Deacetylase Inhibitor Depsipeptide Has Differential Activity in Specific Cytogenetic Subsets of Acute Myeloid Leukemia (AML).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 264-264 ◽  
Author(s):  
Olatoyosi M. Odenike ◽  
Serhan Alkan ◽  
Dorie Sher ◽  
John E. Godwin ◽  
Dezheng Huo ◽  
...  
Keyword(s):  
Histone Deacetylase Inhibitor ◽  
Histone Deacetylases ◽  
Target Genes ◽  
Mononuclear Cells ◽  
Chromosomal Abnormalities ◽  
Dna Hypermethylation ◽  
Deacetylase Inhibitor ◽  
Group A ◽  
Group B ◽  
Bone Marrow Blasts

Abstract Recruitment of histone deacetylases and DNA hypermethylation of promoter regions of specific genes are two mechanisms of transcriptional repression and gene silencing which have been linked, and are implicated in differentiation block in AML. We hypothesized that the histone deacetylase inhibitor (HDI) depsipeptide could result in transcriptional de-repression, upregulation of specific target genes and differentiation of the leukemic clone in AML. Eighteen patients (pts), median age 60 years (range 25–77) with relapsed or refractory AML were enrolled on a multicenter Phase II study of depsipeptide in AML. Patients were stratified into 2 groups on study entry: Group A (n=14) included patients without specific chromosomal abnormalities known to recruit histone deacetylases. Group B (n=4) included patients with chromosomal aberrations such as the t(8;21), inv 16 and t(15;17) known to recruit histone deacetylases. Depsipeptide was administered intravenously at a dose of 18mg/m2/d on days 1, 8 and 15 of a 28 day cycle. Peripheral blood mononuclear cells were obtained prior to (hour 0), and after 4 (hr 4) and 24 hrs (hr 24), on days 1 and 8 of the first cycle of therapy for evaluation of histone acetylation by flow cytometry, and gene re-expression by REAL-time RT-PCR. Target genes of interest include MDR1, a target of HDI mediated upregulation, and p15INK4B (p15), a target of DNA hypermethylation in AML. MDR1 and p15 copy numbers are expressed as a normalized quotient of MDR1 and p15, respectively, to the housekeeping gene ABL. The drug has been well tolerated. The most common adverse effects noted included grade 1/2 nausea, vomiting and fatigue. No objective evidence of response (CR or PR) or other evidence of antileukemic activity has been seen in group A. In contrast, 2 of 4 pts (50%) in Group B, have had a disappearance of bone marrow blasts (blast percentage &lt; 5%) in the setting of a normocellular marrow, with concomitant recovery of near-normal hematopoiesis following 1 and 2 cycles of therapy respectively. This anti-leukemic effect was short-lived, with both pts developing an increase in bone marrow blasts within 30 days of the initial response. Both of these patients also had translocations involving the AML1 gene {1 had t(8;21) and the other had a novel translocation t(4;21)}. Interestingly both of these responding pts and one other pt (75%) in cohort B demonstrated an increase in H3 acetylation at 4 and/or 24 hrs, in contrast to 4 of 14 pts (28%) in cohort A. There was an overall mean increase of 41% in MDR1 expression at hr 4 on days 1 and 8 (p=0.04). p15 expression was also upregulated at hr 4 on days 1 and 8 (91% mean increase, p=0.01). We conclude that the HDI, depsipeptide, may have anti-leukemic activity in specific cytogenetic subsets of AML known to recruit histone deacetylases, and this is associated with a concomitant increase in histone acetylation. In addition, upregulation of specific target genes occurred in patient derived mononuclear cells, following depsipeptide treatment. The study remains open to accrual for pts with specific chromosomal abnormalities known to recruit histone deacetylases.

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