Phase II Evaluation of the Tyrosine Kinase Inhibitor MLN518 in Patients with Acute Myeloid Leukemia (AML) Bearing a FLT3 Internal Tandem Duplication (ITD) Mutation.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1792-1792 ◽  
Author(s):  
Daniel J. De Angelo ◽  
Richard M. Stone ◽  
Mark L. Heaney ◽  
Stephen D. Nimer ◽  
Ronald Paquette ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Steady State ◽  
Phase Ii ◽  
Plasma Concentrations ◽  
Remission Induction ◽  
Western Blots ◽  
Adequate Treatment ◽  
The Mean ◽  
Trough Plasma ◽  
Bone Marrow Blasts

Abstract MLN518 is a small molecule inhibitor of FLT3, PDGFR and c-Kit that is currently being evaluated as a therapy for AML. Previous phase I evaluation of MLN518 showed that it inhibits the phosphorylation of both wild-type and ITD-mutated FLT3 in patients’ leukemic blasts with an IC90 in the range of 100–175 ng/mL. Anti-leukemic activity was also observed, with decreases in both peripheral and bone marrow blasts. Dose-limiting toxicity, consisting of reversible general muscular weakness and/or fatigue was associated with trough plasma MLN518 concentrations > 1000 ng/mL. We are now conducting a phase II study of MLN518 in patients with relapsed or refractory AML and in untreated patients with AML considered unfit for standard AML therapies. Eligibility requires demonstration of the FLT3 ITD mutation in the patient’s blasts. All patients are treated with MLN518 at an initial dose of 525 mg po bid, with provision for dose reduction if MLN518-associated weakness occurs. Twenty patients have been treated with MLN518 in this study, eighteen of whom are currently evaluable (2 patients have recently started therapy). Toxicities associated with MLN518 therapy have included weakness/fatigue, QTc prolongation (relationship to MLN518 uncertain), and nausea and vomiting. MLN518 plasma concentration-time data for the first fourteen patients demonstrates that all patients achieved steady-state trough plasma concentrations > 150 ng/mL. Both inter- and intra-subject variability (%CV) in trough steady-state concentrations were < 30%. Assessment of total and phosphorylated FLT3 in leukemic blasts isolated from peripheral blood was possible in 4 patients. Western blots from blasts obtained before and after MLN518 dosing demonstrated either partial or complete inhibition of FLT3 phosphorylation with MLN518 plasma concentrations > 130 ng/mL. Of the eighteen evaluable patients, response could not be assessed in three because intercurrent illness and/or MLN518-associated toxicity precluded adequate treatment with MLN518 (≥ 14 days). Seven patients experienced progressive AML without evidence of any anti-leukemic effect. Two patients had stable disease for ≥ 50 days and subsequently underwent bone marrow transplantation. Although no complete or partial remissions have been observed, 6 patients have demonstrated evidence of an anti-leukemic effect with decreases in both peripheral and bone marrow blasts of 1-3 months duration. In these 6 patients the mean decrease in the absolute peripheral blast count was 92%, with a range of 85–100%. The mean decrease in the bone marrow blast percentage was 62%, with a range of 44–94%. We conclude that MLN518 has anti-leukemic activity in FLT3 ITD-mutated AML and should be further evaluated as a component of remission-induction and/or maintenance therapy in this disease.

scholarly journals Comparison of Plasma, Epithelial Lining Fluid, and Alveolar Macrophage Concentrations of Solithromycin (CEM-101) in Healthy Adult Subjects

2012 ◽  
Vol 56 (10) ◽  
pp. 5076-5081 ◽  
Author(s):  
Keith A. Rodvold ◽  
Mark H. Gotfried ◽  
J. Gordon Still ◽  
Kay Clark ◽  
Prabhavathi Fernandes
Keyword(s):  
Steady State ◽  
High Performance ◽  
Healthy Adult ◽  
Plasma Concentrations ◽  
Epithelial Lining ◽  
Time Curve ◽  
Epithelial Lining Fluid ◽  
Once Daily ◽  
Drug Concentrations ◽  
The Mean

ABSTRACTThe steady-state concentrations of solithromycin in plasma were compared with concomitant concentrations in epithelial lining fluid (ELF) and alveolar macrophages (AM) obtained from intrapulmonary samples during bronchoscopy and bronchoalveolar lavage (BAL) in 30 healthy adult subjects. Subjects received oral solithromycin at 400 mg once daily for five consecutive days. Bronchoscopy and BAL were carried out once in each subject at either 3, 6, 9, 12, or 24 h after the last administered dose of solithromycin. Drug concentrations in plasma, ELF, and AM were assayed by a high-performance liquid chromatography-tandem mass spectrometry method. Solithromycin was concentrated extensively in ELF (range of mean [± standard deviation] concentrations, 1.02 ± 0.83 to 7.58 ± 6.69 mg/liter) and AM (25.9 ± 20.3 to 101.7 ± 52.6 mg/liter) in comparison with simultaneous plasma concentrations (0.086 ± 0.070 to 0.730 ± 0.692 mg/liter). The values for the area under the concentration-time curve from 0 to 24 h (AUC0–24values) based on mean and median ELF concentrations were 80.3 and 63.2 mg · h/liter, respectively. The ratio of ELF to plasma concentrations based on the mean and median AUC0–24values were 10.3 and 10.0, respectively. The AUC0–24values based on mean and median concentrations in AM were 1,498 and 1,282 mg · h/L, respectively. The ratio of AM to plasma concentrations based on the mean and median AUC0–24values were 193 and 202, respectively. Once-daily oral dosing of solithromycin at 400 mg produced steady-state concentrations that were significantly (P< 0.05) higher in ELF (2.4 to 28.6 times) and AM (44 to 515 times) than simultaneous plasma concentrations throughout the 24-h period after 5 days of solithromycin administration.

Detection of Clonal Hematopoiesis in Cytopenic Patients Using Targeted Sequencing

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1654-1654
Author(s):  
Eric J. Duncavage ◽  
Jennifer O'Brien ◽  
Kiran R. Vij ◽  
Chris A Miller ◽  
Jin Shao ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Clinical Diagnosis ◽  
Somatic Mutation ◽  
Somatic Mutations ◽  
World Health ◽  
Low Grade ◽  
Clonal Hematopoiesis ◽  
The Mean ◽  
Normal Cytogenetics ◽  
Bone Marrow Blasts

Abstract Introduction: The clinical diagnosis of myelodysplastic syndrome (MDS) relies on the presence of persistent cytopenias, not otherwise explained, and evidence of morphologic dysplasia in the bone marrow. Low grade MDS (bone marrow blasts <5%) is defined by the presence of morphologic dysplasia in at least 10% of cells in one or more cell lineage. Low grade MDS is particularly challenging to diagnose, as morphologic dysplasia may be subtle and is subject to high inter-observer variability. The ability to diagnose low grade MDS can be improved by incorporating cytogenetic evaluation of the bone marrow, especially in the setting of equivocal morphologic dysplasia. However, many MDS cases (up to 60%) lack cytogenetic abnormalities, limiting the overall utility of cytogenetics. Multiple recent studies have demonstrated that the majority of MDS patients (over 80% in some studies) harbor recurrent somatic mutations in a core group of genes. We sought to determine if targeted DNA sequencing of genes recurrently mutated in MDS and AML could be useful in the evaluation of cytopenic patients with a normal karyotype being evaluated for the possible diagnosis of MDS. Methods: We screened patients who presented for evaluation of MDS between 2002 and 2014 that had consented for sequencing studies and had banked samples. Patients were selected based on 1) World Health Organization defined cytopenia (WBC <1,800/µL, hemoglobin <10g/dL, platelets <100k/µL) in at least one lineage, 2) bone marrow blasts <5%, 3) WBC <14k/uL, 4) normal cytogenetics, and 5) absence of prior therapy for MDS. Bone marrow specimens were independently re-reviewed by two board certified hematopathologists. DNA was extracted from cryopreserved bone marrow and skin (to serve as a source of normal DNA) and enriched for a panel of 285 commonly mutated myeloid genes. Captured DNA libraries were sequenced on a HiSeq 2500 instrument with 2x101bp reads. The resulting data was analyzed for single nucleotide variants (SNVs) and insertions/deletions (indels) using VarScan2 in paired normal mode. Results: Thirty-eight patients met the selection criteria, and 30 of these had bone marrow aspirates available for morphologic review and were included in the study. A mean unique coverage depth of 913x was achieved for targeted genes and all reported variants had >50x coverage, variant allele fractions (VAFs) >3%, and minor allele frequencies (MAFs) < 1% in any population. Of the 30 sequenced cases, 25 had a somatic mutation in at least one gene (mean 3.3 mutations/case, range 1-10 mutations/case). The most commonly mutated gene was TET2 (7 cases), followed by ASXL1 (5 cases), EZH2 (4 cases), SRSF2 (4 cases), and U2AF1 (4 cases). Of the 285 sequenced genes, 44 were mutated in at least one case, and 14 were mutated in 2 or more cases. The mean VAF (variant reads/total reads) of detected mutations was 27% (range 3-98%). Morphologic review demonstrated definitive dysplasia (≥10% of cells in least one lineage) made by two pathologists in 18 of 30 cases (supporting the clinical diagnosis of MDS), no dysplasia in 6 of 30 cases, and equivocal dysplasia (where hematopathologists did not agree that dysplasia was ≥10%) in 6 of 30 cases. Thirteen of 18 cases (72%) with definitive dysplasia had a mutation, 5/6 cases (83%) without dysplasia had mutations, and 6/6 (100%) cases with equivocal dysplasia harbored somatic mutations. The mean VAF of mutations was 17.5% in cases without dysplasia, 29% in cases with equivocal dysplasia, and 28% in cases with definitive dysplasia. All of these groups included mutations in canonical MDS genes such as TET2, DNMT3A, SRSF2, RUNX1, and EZH2. Conclusions: In this cohort of 30 cytopenic patients with normal cytogenetics, 80% harbored a somatic mutation in at least one myeloid-associated gene. Somatic mutations were detected in 5 of 6 cases without definitive dysplasia (<10% dysplasia) and 6 of 6 cases with equivocal dysplasia. Notably, canonical MDS mutations were found even in the absence of dysplasia. These findings suggest that clonal hematopoiesis may be present in the majority of cytopenic patients independent of dysplasia, a finding that requires independent validation. Identification of somatic gene mutations in patients with morphologically equivocal MDS or cytopenic patients without definitive dysplasia provides a means for tracking clonal disease that could be used to monitor patients for subsequent development of definitive MDS. Disclosures Duncavage: DI&P Consulting: Consultancy; Cofactor Genomics: Consultancy. Jacoby:Sunesis: Research Funding; Novo Nordisk: Consultancy.

scholarly journals Risk Factors for a Low Linezolid Trough Plasma Concentration in Acute Infections

2013 ◽  
Vol 57 (4) ◽  
pp. 1913-1917 ◽  
Author(s):  
Laura Morata ◽  
Marta Cuesta ◽  
Jhon F. Rojas ◽  
Sebastian Rodriguez ◽  
Merce Brunet ◽  
...  
Keyword(s):  
Risk Factors ◽  
Steady State ◽  
Plasma Concentration ◽  
Plasma Concentrations ◽  
Time Curve ◽  
Content Type ◽  
Acute Infections ◽  
Trough Plasma Concentration ◽  
Dependent Activity ◽  
Trough Plasma

ABSTRACTLinezolid is an antibiotic with time-dependent activity, and both the percentage of time that plasma concentrations exceed the MIC and the area under the concentration-time curve over 24 h in the steady state divided by the MIC (AUC24/MIC ratio) are associated with clinical response. The aim of this study was to analyze the linezolid trough plasma concentration (Cmin) and to determine factors associated with aCmin< 2 mg/liter and other clinically relevant thresholds. Characteristics of 78 patients receiving 600 mg/12 h of linezolid with aCmindetermination at the steady state and within the first 10 days of treatment were retrospectively reviewed. Concentrations were measured using high-pressure liquid chromatography. Univariate and multivariate analysis were performed to identify risk factors of lowCmin. A total of 29.5% of patients had aCmin< 2 mg/liter. The percentage was significantly higher in patients with an estimated glomerular filtration (eGF) > 80 ml/min, in intensive care unit (ICU) patients, and in patients with an infection due toStaphylococcus aureus. The independent predictors ofCmin< 2 mg/liter were an eGF > 80 ml/min (odds ratio [OR], 10; 95% confidence interval [CI], 2.732 to 37.037;P= 0.001) and infection due toS. aureus(OR, 5.906; 95% CI, 1.651 to 21.126;P= 0.006). A linezolidCminof <2 mg/liter was found in 29.5% of cases, and the risk was significantly higher among those with an eGF > 80 ml/min and in infections due toS. aureus. In patients with severe sepsis, a loading dose or continuous infusion and drug monitoring could improve the pharmacodynamic parameters associated with linezolid efficacy.

scholarly journals Pharmacokinetics and Safety of a 7-Day Administration of Intravenous Itraconazole followed by a 14-Day Administration of Itraconazole Oral Solution in Patients with Hematologic Malignancy

2001 ◽  
Vol 45 (3) ◽  
pp. 981-985 ◽  
Author(s):  
Marc A. Boogaerts ◽  
Johan Maertens ◽  
Ronald Van Der Geest ◽  
Andre Bosly ◽  
Jean-Louis Michaux ◽  
...  
Keyword(s):  
Steady State ◽  
Hematologic Malignancy ◽  
Oral Treatment ◽  
Hematologic Malignancies ◽  
Oral Solution ◽  
Once Daily ◽  
Intravenous Treatment ◽  
Good Safety Profile ◽  
The Mean ◽  
Trough Plasma

ABSTRACT The pharmacokinetics and safety of an intravenous hydroxypropyl-β-cyclodextrin solution of itraconazole administered for 7 days followed by itraconazole oral solution administered at 200 mg once or twice daily for 14 days were assessed in 17 patients with hematologic malignancies. Steady-state plasma itraconazole concentrations were reached by 48 h after the start of intravenous treatment. The mean trough plasma itraconazole concentration at the end of the intravenous treatment was 0.54 ± 0.20 μg/ml. This concentration was not maintained during once-daily oral treatment but increased further in the twice-daily treatment group, with a trough itraconazole concentration of 1.12 ± 0.73 μg/ml at the end of oral treatment. As expected in the patient population studied, all patients experienced some adverse events (mainly gastrointestinal). Biochemical and hematologic abnormalities were frequent, but no consistent changes occurred. In conclusion, 7 days of intravenous treatment followed by 14 days of twice-daily oral treatment with itraconazole solution enables plasma itraconazole concentrations of at least 0.5 μg/ml to be reached rapidly and to be maintained. The regimen is well tolerated and has a good safety profile.

scholarly journals Phase II Multicenter Randomized Controlled Clinical Trial on the Efficacy of Intra-articular Injection of Autologous Bone Marrow Mesenchymal Stem Cells with Platelet Rich Plasma for the Treatment of Knee Osteoarthritis

2020 ◽  
Author(s):  
José María Lamo-Espinosa ◽  
Juan F. Blanco ◽  
Mikel Sánchez ◽  
Victoria Moreno ◽  
Froilán Granero-Moltó ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Bone Marrow ◽  
Clinical Trials ◽  
Knee Osteoarthritis ◽  
Phase Ii ◽  
Stromal Cells ◽  
Platelet Rich Plasma ◽  
X Ray ◽  
The Mean

Abstract Background: Mesenchymal stromal cells are a safe and promising option to treat knee osteoarthritis as previously demonstrated in different clinical trials. However, their efficacy, optimal dose and addition of adjuvants must be determined. Here, we evaluated the clinical effects of a dose of 100x106 bone marrow mesenchymal stromal cells (BM-MSCs) in combination with Platelet Rich Plasma (PRGF®) as adjuvant in a randomized clinical trial.Methods: A phase II, multicenter, randomized clinical trial with active control was conducted. Sixty patients diagnosed with knee OA were randomly assigned to 3 weekly doses of PRGF® or intraarticular administration of 100x106 cultured autologous BM-MSCs plus PRGF®. Patients were followed up for 12 months, and pain and function were assessed using VAS and WOMAC and by measuring the knee range of motion range. X-ray and magnetic resonance imaging analyses were performed to analyze joint damage.Results: No adverse effects were reported after BM-MSC administration or during follow-up. According to VAS, the mean value (SD) for PRGF® and BM-MSC with PRGF® went from 5 (1.8) to 4.5 (2.2) (p=0.389) and from 5.3 (1.9) to 3.5 (2.5) (p=0.01), respectively at 12 months.. In WOMAC, the mean (SD) baseline and 12-month overall WOMAC scores in patients treated with PRGF® was 31.9 (16.2) and 22.3 (15.8) respectively (p=0.002) while that for patients treated with BM-MSC plus PRGF® was 33.4 (18.7) and 23.0 (16.6) (p=0.053). Although statistical significances between groups have been not detected, only patients being treated with BM-MSC plus PRGF® could be considered as a OA treatment responders following OARSI criteria. X-ray and MRI (WORMS protocol) revealed no changes in knee joint space width or joint damage.Conclusions: Treatment with BM-MSC associated with PRGF® was shown to be a viable therapeutic option for osteoarthritis of the knee, with clinical improvement at the end of follow-up. Further phase III clinical trials would be necessary to confirm the efficacy. Clinical Trials.gov identifier NCT02365142. Nº EudraCT: 2011-006036-23

scholarly journals Lack of effect of concomitant zidovudine on rifabutin kinetics in patients with AIDS-related complex.

1996 ◽  
Vol 40 (6) ◽  
pp. 1397-1402 ◽  
Author(s):  
R C Li ◽  
S Nightingale ◽  
R C Lewis ◽  
D C Colborn ◽  
P K Narang
Keyword(s):  
Human Immunodeficiency Virus ◽  
Steady State ◽  
Plasma Concentrations ◽  
Urinary Recovery ◽  
Immunodeficiency Virus ◽  
Aids Related Complex ◽  
Safety Parameters ◽  
The Mean ◽  
Interval Ratio ◽  
Related Complex

The effect of concomitant dosing with the antiretroviral agent zidovudine (ZDV) on the pharmacokinetics of rifabutin (RBT) was investigated under steady-state conditions. Sixteen human immunodeficiency virus-positive patients with AIDS-related complex who had been maintained on stable ZDV therapy for > or = 6 weeks were administered RBT concomitantly for 12 days. Eight patients received daily doses of 300 or 450 mg of RBT. Administration of ZDV was discontinued on day 13, and RBT was given alone for 3 additional days. Four patients receiving 450 mg of RBT discontinued treatment. Under steady-state ZDV and RBT dosing, safety and kinetics assessments were performed on day 13 (ZDV plus RBT) and day 16 (RBT alone). Kinetics on days 13 and 16 demonstrated that RBT (300 or 450 mg) was readily absorbed, with the time at which the plasma concentration was maximal (Tmax) ranging between 2.6 and 2.9 h. At these two doses, the mean steady-state maximal plasma concentrations (Cmax) were 250 and 430 ng/ml on day 13 and 245 and 458 ng/ml on day 16, respectively. RBT kinetics at the two doses were proportional and similar on the basis of estimates of the ratios of the areas under the concentration-time curves over the dosing interval from 0 to 24 h (AUC0-24) (450 mg/300 mg), which were 1.5 and 1.4 for days 13 and 16, respectively. No significant differences were apparent in the mean oral clearance (CLs/F) estimates (range, 1.60 to 1.77 liters/h/kg), which were dose independent and similar for the 2 assessment days, as was the urinary recovery of RBT and its 25-deacetyl metabolite. Low urinary recovery of 25-deacetyl RBT and an AUC metabolite/parent ratio of 0.1 suggest that there is minimal metabolism of RBT via the deacetylation pathway. For RBT, pooled mean (95% confidence interval) ratio (day 13/day 16) estimates for Cmax, Tmax, AUC0-24, and CLs/F were 1.07 (range, 0.77 to 1.38), 1.08 (0.89 to 1.27), 0.97 (0.82 to 1.13), and 1.09 (0.92 to 1.26), respectively. In addition, no significant changes in any of the major safety parameters were detected throughout the study. Therefore, it is concluded that coadministration of ZDV and RBT does not affect the pharmacokinetics and/or safety of RBT in human immunodeficiency virus-positive patients.

A humanized unconjugated antibody targeting CD33 (SGN-33; huM195) is active in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 16500-16500
Author(s):  
A. Raza ◽  
N. Galili ◽  
J. G. Jurcic ◽  
G. J. Roboz ◽  
B. L. Wood ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Dose Escalation ◽  
Myeloid Leukemia ◽  
Antibody Dependent Cellular Cytotoxicity ◽  
Monocytic Cells ◽  
Complement Dependent Cytotoxicity ◽  
The Mean ◽  
Higher Doses ◽  
Dose Limiting Toxicity ◽  
Bone Marrow Blasts

16500 Background: CD33 is a sialoglycan protein expressed on normal myeloid and monocytic cells as well as the vast majority of myeloid malignancies. A humanized antibody has been developed that recognizes CD33 and induces antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. In prior clinical testing, this antibody led to significant reductions in blasts in patients with relapsed and refractory AML. Methods: A phase I single-arm dose escalation trial was initiated at multiple sites to assess the safety, immunogenicity, pharmacokinetics, and activity of SGN-33 at higher doses than previously tested. Cohorts of 3–6 patients with advanced MDS or AML will receive intravenous SGN-33 at weekly doses of 1.5 to 8 mg/kg over 5 weeks. Clinical response will be determined by bone marrow morphology and hematologic improvement. Responding patients will be eligible for 4 additional infusions. Results: Treatment of 6 patients at 1.5 mg/kg/wk has been well-tolerated, with no dose-limiting toxicity or related adverse events > grade 2. The median age is 79.5 years (range 52–88), and all patients were previously untreated. One patient discontinued treatment because of refractory thrombocytopenia, unrelated to SGN-33. CD33 saturation of the bone marrow blasts after 2 infusions ranged from 27% to 84% with an average of 55%. The mean change in bone marrow blasts by flow cytometry after 2 weeks was −9% (range −68% to +44%; N = 5), and the marrow monocytes changed by −39% (range −90% to +86%; N = 5). Two patients have completed re-staging after cycle 1. Blasts decreased from 29% to 12% in an 88 year-old woman with AML and from 11% to 9% in a 79 year-old man with RAEB. Conclusions: SGN-33 is well tolerated at 1.5 mg/kg/wk, and dose escalation is ongoing. Antitumor activity was seen in elderly patients with previously untreated AML and MDS. Incomplete saturation of the CD33 on bone marrow blasts suggests that higher doses may improve efficacy. SGN-33 holds promise for the treatment of patients with myeloid malignancy who are ineligible for aggressive therapy. [Table: see text]

Improved Remission Induction Rate of Childhood AML: Preliminary Results of the AML02 Trial.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 275-275 ◽  
Author(s):  
Jeffrey Rubnitz ◽  
Bassem Razzouk ◽  
Paul Bowman ◽  
Gary Dahl ◽  
Norman Lacayo ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Low Dose ◽  
Single Agent ◽  
Remission Induction ◽  
Intrathecal Therapy ◽  
High Dose ◽  
Triple Combination Therapy ◽  
Cns Relapse ◽  
Low Dose Cytarabine ◽  
Bone Marrow Blasts

Abstract The multicenter AML02 trial randomly assigns patients to receive high-dose or low-dose cytarabine (A), daunorubicin (D), and etoposide (E) as Induction I; all subsequent therapy is risk-adapted. Pharmacokinetic, pharmacodynamic, and gene expression studies are performed after exposure to high-dose or low-dose cytarabine. Patients with no response (NR, ≥ 25% bone marrow blasts) to Induction I receive low-dose ADE + gemtuzumab ozogamicin (GO) as Induction II, whereas all others receive ADE. Minimal residual disease (MRD) is monitored by flow cytometry and is defined as ≥ 0.1% cells with leukemia-associated immunophenotypes among bone marrow mononuclear cells. Patients who are MRD+ after induction therapy receive GO as a single agent before consolidation chemotherapy or stem cell transplantation. Among the 112 patients enrolled since October 2002, 37 had -7, FAB M6 or M7, FLT3 internal tandem duplication (ITD), or MDS or treatment-related AML and were classified as high-risk (HR); 32 had AML1-ETO, CBFβ-MYH11, or MLL-AF9 (low-risk; LR); the remaining 43 were considered as standard-risk (SR). The rate of complete response (CR, &lt;5% bone marrow blasts) was 84% after Induction I and 97% after Induction II. Of the 3 patients who did not attain CR, 2 had partial responses and 1 died of streptococcal sepsis during Induction II. CR rates differed according to risk group after Induction I (LR, 100%; SR, 91%, HR 61%) but not after Induction II (LR, 100%; SR, 98%, HR 94%). The association between risk groups and MRD (determined successfully in 95% of cases) was more striking: the rate of MRD negativity after Induction I was 88% in LR, 59% in SR, and 26% in HR patients; after Induction II, rates were 97%, 82%, and 53%, respectively. Response to initial therapy was particularly poor among patients with a FLT3-ITD: only 1 of 11 patients was MRD-negative after Induction I and only 3 were MRD-negative after Induction II. 5 of the 6 patients who had NR to Induction I attained CR after subsequent treatment with ADE + GO and all 6 had dramatic reductions in MRD levels (from a median of 26% to a median of 0.24%). An additional 14 patients with MRD levels 0.1% to 5.6% received GO at the beginning of consolidation: 9 became MRD-negative. Overall, there were 4 deaths from infection (2 bacterial, 1 fungal, 1 viral), which occurred during induction (1), consolidation (1), and after completion of chemotherapy (2). Because CNS relapse occurred in 3 of the first 33 patients treated, intrathecal therapy was changed from cytarabine alone to triple combination therapy with methotrexate, hydrocortisone, and cytarabine; none of the 79 subsequent patients has had a CNS relapse. The 1-year event-free and overall survival estimates are 76.8% (SE, 5.1%) and 89.1% (SE, 3.8%). In conclusion, AML02 therapy has produced a high overall remission rate and low treatment-related mortality, which we attribute to excellent supportive care and to the use of risk- and MRD-adapted therapy.

A Phase II Study of Azacitidine (Vidaza™) for Patients with Myelofibrosis (MF).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2706-2706 ◽  
Author(s):  
Alfonso Quintas-Cardama ◽  
Hagop Kantarjian ◽  
Guillermo Garcia-Manero ◽  
Deborah Thomas ◽  
STeven Kornblau ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Phase Ii ◽  
Retinoic Acid Receptor ◽  
Jak2 V617f ◽  
Complete Response ◽  
Pegylated Interferon ◽  
Prior Therapy ◽  
Grade 3 ◽  
Wbc Count ◽  
Bone Marrow Blasts

Abstract Aberrant DNA methylation of promoter-associated CpG islands is a mechanism of epigenetic silencing frequently encountered in human neoplasia. Hypermethylation of several genes such as p15INK4B, p16INK4A, progesterone receptor, and the retinoic acid receptor β have been detected in patients (pts) with advanced-stage MF. Azacitidine (Vidaza™) is a hypomethylating agent that induces reactivation of methylated genes and has been approved for the treatment of pts with myelodysplastic syndromes. The objective of this phase II trial was to study the efficacy of azacitidine in pts with relapsed or refractory MF (primary, or secondary to essential thrombocythemia or polycythemia vera) or newly-diagnosed with a Lille risk score 1 or 2 (risk factor are white blood cell [WBC] count >30x109/L or <4x109/L, and hemoglobin [Hb] <10 g/dL). Azacitidine was given at 75 mg/m_ daily (dose level [DL] 0) for 7 days every 4 weeks for 6 cycles but this could be reduced to 50 (DL -1), 25 (DL -2), or 12.5 (DL -3) or increased to 100 (DL +1) mg/m_ according to toxicity or lack of response, respectively. Thirty-four pts have been treated, median age 66 years (range 39–82), time from MF diagnosis to azacitidine therapy 21 months (range 1–361), median Hb 10.3 g/dL (range 8.2–14.3), WBC 10.7x109/L (range 1.7–57.7), and platelets 205x109/L (range 11–1216). Pts had received a median of 1 prior therapy (range 0–6), including hydroxyurea (HU; n=16), anagrelide (AG; n=8), lenalidomide (n=6), thalidomide (n=6), etanercept (n=2), and pegylated interferon (n=2). Six pts had not received any prior therapy. The JAK2 V617F mutation was detected in 19 (70%) of 27 tested pts and 12 of 34 (35%) had abnormal cytogenetics. A total of 142 cycles have been administered. All 34 patients are evaluable for response and toxicity. Responses have been observed in 10 (29%) pts so far, including complete response (CR) in 1 (normal blood counts and <5% bone marrow blasts; off HU, AG, growth factors, and no transfusions), partial response (PR) in 7 (defined as at least 2 of the following: Hb increase by ≥2 g/dL, 50% increase in platelets, decrease of bone marrow blasts or organomegaly by ≥50%, normalization of WBC count without blasts, or reduction in bone marrow fibrosis), and hematologic improvement (HI) in 2 (defined as at least 2 of the following: decrease by ≥25% of pretreatment leukocytosis, splenomegaly, or marrow blasts, or increase of Hb by ≥1g/dl or platelets by ≥25%). The median time to best response was 7.5 weeks (range, 3 to 26). Fifteen (44%) pts discontinued azacitidine due to: lack of response in 7, transformation to acute myeloid leukemia in 2, death (unrelated to azacitidine therapy) in 1, pt’s decision in 1, grade 3–4 toxicity in 2, and other medical reasons in 2. Azacitidine has been generally well tolerated; 10 pts (29%) had grade 3 or 4 toxicity; neutropenia was the only grade 4 toxicity (in 4 pts). Eleven pts (32%) have required dose reduction to DL -1, of which 3 reduced to DL -2, and 9 pts (26%) escalated the dose to DL +1. In summary, azacitidine is well tolerated and has activity in a subset of pts with MF, with current overall response rate of 29%. Updated clinical results will be presented.

Sign in / Sign up

Export Citation Format

Share Document