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Elihu H Estey

Publications and source records attributed to Elihu H Estey.

At least 19 recordsLinked to original sources
PubMed2006

The clinical spectrum of adult acute myeloid leukaemia associated with core binding factor translocations.

To better understand the spectrum of adult acute myeloid leukaemia (AML) associated with core binding factor (CBF) translocations, 370 patients with newly diagnosed CBF-associated AML were analysed. Patients' age ranged from 16-83 years (median 39 years) with a slight male predominance (55%); 53% had inv(16); 47% had t(8;21). Patients with t(8;21) tended to be younger (P = 0.056), have lower peripheral blood white cell counts (P < 0.0001) and were more likely to have additional cytogenetic abnormalities (P < 0.0001). Loss of sex chromosome, del(9q) and complex abnormalities were more common among patients with t(8;21), while +22 and +21 were more common with inv(16). Overall, 87% [95% confidence interval (CI) 83-90%] of patients achieved complete response (CR) with no difference between t(8;21) and inv(16); however, the CR rate was lower in older patients due to increased resistant disease and early deaths. Ten-year overall survival (OS) was 44% (95% CI 39-50%) and, in multivariate analysis, was shorter with increasing age (P < 0.0001), increased peripheral blast percentage (P = 0.0006), in patients with complex cytogenetic abnormalities in addition to the CBF translocation (P = 0.021), and in patients with t(8;21) (P = 0.025). OS was superior in patients who received regimens with high-dose cytarabine, a combination of fludarabine and intermediate-dose cytarabine, or haematopoietic cell transplantation.

Acute Disease↗
PubMed2006

High-dose cytosine arabinoside in the treatment of acute myeloid leukemia: Review of three randomized trials.

BACKGROUND: The use of high-dose cytosine arabinoside (HDAraC) during induction may improve outcomes in patients with acute myeloid leukemia (AML) compared with standard-dose AraC (SDAraC). The objective of this review was to assess the impact of HDAraC during induction therapy for patients with AML based on results from randomized trials. METHODS: All randomized trials in the field were identified by using a predefined search strategy. Trials that assessed the impact of HDAraC compared with SDAraC as induction therapy for adult patients with AML in a randomized fashion and that reported the relevant endpoints were included. Data were extracted from each trial by both reviewers according to prespecified criteria. RESULTS: No differences between HDAraC and SDAraC were found with regard to complete remission rates (relative risk, 1.00; 95% confidence interval [95% CI], 0.92-1.10). The weighted mean difference (WMD) for median recurrence-free survival (RFS) was 4.19 in favor of HDAraC (95% CI, 0.59-7.78; P = .02). The WMD for 4-year RFS was 10.98 in favor of HDAraC (95% CI, 1.02-20.94; P = .03). The WMD for median overall survival (OS) was - 0.22 for HDAraC compared with SDAraC (95% CI, - 2.76-2.32; P = .9). Data regarding the median OS was heterogeneous between studies (chi-square P = .00), with 2 studies in favor of HDAraC and 2 studies in favor of SDAraC. The WMD for 4-year OS was 6.21 in favor of HDAraC (95% CI, 2.70-9.72; P = .0005). CONCLUSIONS: Induction therapy with HDAraC improved long-term disease control and overall survival in adults age < 60 years with de novo AML. It remains unknown whether patients should receive HDAraC during induction or if it is to be given during postremission therapy. Further analyses should focus on this issue and on the effects of HDAraC in prognostically different subgroups of patients with AML.

Adolescent↗
PubMed2006

Simultaneous activation of multiple signal transduction pathways confers poor prognosis in acute myelogenous leukemia.

Deregulation of signal transduction pathways (STPs) may promote leukemogenesis by conferring cell proliferation and survival advantages in acute myelogenous leukemia (AML). Several agents targeting STPs are under development; however, redundancy and cross-talk between STPs could activate multiple downstream effectors and this could negate the effect of single-target inhibition. The frequency of concurrent activation of multiple STPs in AML and the prognostic relevance of STP activation in AML are unknown. STP protein expression (PKCalpha, ERK2, pERK2, AKT, and pAKT) was measured by Western blot in samples from 188 patients with newly diagnosed, untreated AML. In univariate and multivariate analysis high levels of PKCalpha, ERK, pERK, and pAKT, but not AKT, were adverse factors for survival as was the combination variable PKCalpha-ERK2&pERK2-pAKT. Survival progressively decreased as the number of activated pathways increased. Patients were more likely to have none or all 3 pathways activated than was predicted based on the frequency of individual pathway activation, strongly suggesting that cross-activation occurred. Simultaneous activation of multiple STPs is common in AML and has a progressively worse adverse effect on prognosis. It is thus likely that only combinations of agents that target the multiply activated STPs will be beneficial for patients with AML.

Aged↗
PubMed2006

General approach to, and perspectives on clinical research in, older patients with newly diagnosed acute myeloid leukemia.

Most patients aged>or=55 to 60 years who are treated for newly diagnosed acute myeloid leukemia (AML) receive a combination of an anthracycline plus cytarabine (ara-C). A principal thesis of this chapter is that such therapy is unsatisfactory for the great majority of such patients. In particular, the >or=15% risk of death in the month following the start of treatment is difficult to justify given median survivals of less than 1 year in the patients who do not die early. Thus, investigational therapy should be recommended for most, if not all, older patients. In patients for whom such therapy is not feasible, low-dose ara-C is a reasonable alternative except for patients with de novo disease and a normal karyotype, who might benefit more from an anthracycline+ara-C combination, and patients with either a poor performance status, abnormal organ function, or age>or=80, for whom supportive/palliative care only is recommended. Distinctions are made between investigational therapies likely associated with lower and higher risks of treatment-related mortality (TRM). The former are preferable initial treatment in patients aged 70 and above, or with abnormal cytogenetics. Three topics are discussed that are likely to be relevant to future clinical research in older patients: the possibility of delaying therapy to gain information about prognosis with initial induction therapy, the clinical value of responses less than conventional complete remission (CR), and the possibility of looking for larger differences between treatments in randomized clinical trials.

Acute Disease↗
PubMed2006

Adaptive dose selection using efficacy-toxicity trade-offs: illustrations and practical considerations.

The purpose of this paper is to describe and illustrate an outcome-adaptive Bayesian procedure, proposed by Thall and Cook (2004), for assigning doses of an experimental treatment to successive cohorts of patients. The method uses elicited (efficacy, toxicity) probability pairs to construct a family of trade-off contours that are used to quantify the desirability of each dose. This provides a basis for determining a best dose for each cohort. The method combines the goals of conventional Phase I and Phase II trials, and thus may be called a "Phase I-II" design. We first give a general review of the probability model and dose-finding algorithm. We next describe an application to a trial of a biologic agent for treatment of acute myelogenous leukemia, including a computer simulation study to assess the design's average behavior. To illustrate how the method may work in practice, we present a cohort-by-cohort example of a particular trial. We close with a discussion of some practical issues that may arise during implementation.

Algorithms↗
PubMed2006

Open-label, randomized comparison of itraconazole versus caspofungin for prophylaxis in patients with hematologic malignancies.

Invasive fungal infection remains the most common cause of infectious death in acute leukemia. In this open-label, randomized study, we compared the efficacy and safety of caspofungin with that of intravenous itraconazole for antifungal prophylaxis in patients undergoing induction chemotherapy for acute myelogenous leukemia or myelodysplastic syndrome. Of 200 patients, 192 were evaluable for efficacy (86 for itraconazole, 106 for caspofungin). Duration of prophylaxis (median, 21 days [range, 1 to 38 days]), demographics, and prognostic factors were similar in both groups. Ninety-nine patients completed antifungal prophylaxis without developing fungal infection (44 [51%] with itraconazole, 55 [52%] with caspofungin). Twelve patients developed documented invasive fungal infections, five in the itraconazole group (four with candidemia and one with Aspergillus pneumonia), and seven in the caspofungin group (two with candidemia, two with disseminated trichosporon species, two with Aspergillus pneumonia, and one with disseminated Fusarium spp). Two patients in the itraconazole group and four in the caspofungin group died of fungal infection (P = 0.57). Grade 3 to 4 adverse event rates were comparable between groups; the most common event in both was reversible hyperbilirubinemia. No evidence of cardiovascular toxicity from intravenous itraconazole was noted among patients older than 60. In conclusion, intravenous itraconazole and caspofungin provided similar protection against invasive fungal infection during induction chemotherapy, and both drugs were well tolerated.

Adolescent↗
PubMed2006

Building and validating a prognostic index for biomarker studies.

An important aspect of modern cancer research is identifying molecular and genetic markers that predict an individual's risk of recurrence and response to treatment. Increasingly, a large number of biomarkers are included in studies, even though at most a small proportion of them will be prognostic. This article considers the selection and validation of prognostic biomarkers, and proposes a method for building and validating a prognostic index based on potentially many markers. We use simulation to show that our proposed method controls false-positive rate while retaining reasonable power. The prognostic index gets its power from combining prognostic biomarkers. It can be very powerful even when there are few markers that are predictive.

Biomarkers↗
PubMed2005

Final report of the efficacy and safety of gemtuzumab ozogamicin (Mylotarg) in patients with CD33-positive acute myeloid leukemia in first recurrence.

BACKGROUND: In this study, the authors analyzed the efficacy and safety of gemtuzumab ozogamicin (GO) (Mylotarg), an antibody-targeted chemotherapy for CD33-positive acute myeloid leukemia (AML). METHODS: Patients with CD33-positive AML in first recurrence were entered in 3 open-label, single-arm, Phase II studies. Patients received monotherapy with GO 9 mg/m(2) as a 2-hour intravenous infusion in 2 doses separated by 2 weeks. Patients were evaluated for remission, survival, and treatment-emergent adverse events. RESULTS: Two hundred seventy-seven patients (median age, 61 yrs) were treated with GO, and 71 patients (26%) achieved remission, which was defined as < or = 5% blasts in the bone marrow without leukemic blasts in the peripheral blood, neutrophil recovery to > or = 1500/microL, hemoglobin > or = 9 g/dL, and independence from red blood cell and platelet transfusions. Complete remission (CR) with platelet recovery (> or = 100,000/microL) or without full platelet recovery (< 100,000/microL) (CRp) was observed in 35 patients (13%) and 36 patients (13%), respectively. The median recurrence-free survival was 6.4 months for patients who achieved CR and 4.5 months for patients who achieved CRp. Although expected incidences of Grade 3 or 4 neutropenia (98%) and thrombocytopenia (99%) were observed, the incidence of Grade 3 or 4 sepsis (17%) and pneumonia (8%) was relatively low. Grade 3 or 4 hyperbilirubinemia and hepatic aspartate aminotransferase and alanine aminotransferase elevations were reported in 29%, 18%, and 9% of patients, respectively; 0.9% of patients who did not undergo prior or subsequent hematopoietic stem cell transplantation developed hepatic venoocclusive disease after GO treatment. CONCLUSIONS: When it was administered to patients with CD33-positive AML in first recurrence, single-agent GO induced a 26% remission rate with a generally acceptable safety profile.

Adult↗
PubMed2005

CD34+ cell selection is required to assess HOXA9 expression levels in patients with myelodysplastic syndrome.

Overexpression of HOXA9 is linked to the molecular pathogenesis of acute myeloid leukaemia (AML) and myelodysplastic syndrome (MDS), conferring a poor prognosis. HOXA9 expression levels were analysed in the diagnostic bone marrow (BM) samples of 13 MDS patients. HOXA9 was expressed by CD34(+) BM cells at median levels 3.1-fold higher than in CD34(-) cells from the same patient and at median levels 4.3-fold higher than in CD34(+) cells from healthy donors. These results indicate that CD34(+) cell selection is required to accurately assess the expression levels of HOXA9 and related genes in the multipotential malignant progenitor cells of MDS patients.

Aged↗
PubMed2005

Some ethical issues in phase II trials in acute leukemia.

This paper addresses several scientific and ethical issues that arise in the design and conduct of phase II clinical trials of experimental therapies. Although we discuss chemotherapy trials in acute leukemia, the issues pertain to a much larger class of early-phase clinical trials. Our focus is on the manner in which numerical values of standard and targeted response rates of a statistical design are specified, the number of interim tests that are applied, and the effects of these design features on early stopping probabilities and the treatments that patients actually receive. These points are illustrated by numerical comparisons of alternative designs for a particular phase II trial of a new drug for relapsed or refractory acute myelogenous leukemia. We show that statistical designs that target inappropriately low response rates or that apply early stopping rules too infrequently are at odds with good statistical and medical practice and that such designs often provide less benefit to the patients in the trial than would be obtained by simply treating all patients with standard therapy. The general conclusions are that statistical designs have both scientific and ethical implications, and that science, statistics, and ethics cannot be treated as separate issues.

Acute Disease↗
PubMed2004

Acquired PTPN11 mutations occur rarely in adult patients with myelodysplastic syndromes and chronic myelomonocytic leukemia.

Myelodysplastic syndromes (MDS) are comprised of a heterogeneous group of stem cell disorders characterized by ineffective hematopoiesis and susceptibility to transform to acute myeloid leukemia. The molecular pathways underlying disease initiation and evolution are still largely unknown. We recently demonstrated that acquired mutations in PTPN11 are a major event in JMML and occur with variable prevalence in children with other hematologic malignancies, including MDS. Here, we investigated contribution of PTPN11 mutations to adult MDS and CMML pathogenesis. Our results indicate that PTPN11 lesions might play a role in adult MDS/CMML pathogenesis but do not represent a major molecular event.

Adult↗
PubMed2004

Soluble vascular endothelial growth factor receptor 1, and not receptor 2, is an independent prognostic factor in acute myeloid leukemia and myelodysplastic syndromes.

BACKGROUND: Vascular endothelial growth factor (VEGF) and its receptors (VEGFRs) are major regulators of angiogenesis, which plays a key role in the growth and dissemination of solid tumors and hematologic neoplasms. METHODS: The authors measured the plasma concentrations of soluble VEGFR1 (sVEGFR1) and sVEGFR2 in 133 patients with acute myeloid leukemia (AML) and in 80 patients with myelodysplastic syndromes (MDS) at the time of initial presentation and compared clinical behaviors. RESULTS: A reverse correlation was observed between plasma sVEGFR1 levels and the rate of complete remission (CR) in patients with AML, but not in patients with MDS. In contrast, increased plasma levels of sVEGFR2 were correlated with a lower CR rate in patients with MDS, but not in patients with AML. Cox regression model analysis demonstrated that plasma levels of sVEGFR1, but not sVEGFR2, were independent prognostic factors in both patients with AML and patients with MDS. CONCLUSIONS: The findings suggest that different mechanisms are involved in the pathophysiology of AML and MDS. The concentration of sVEGFR1 and sVEGFR2 in plasma should be considered a significant factor in guiding antiangiogenic therapy for AML and MDS. They may play a role in the pharmacodynamics of therapeutic agents that are supposed to bind directly to these receptors.

Adolescent↗
PubMed2004

Phase II study of R115777, a farnesyl transferase inhibitor, in myelodysplastic syndrome.

PURPOSE: To perform a phase II study of the farnesyl transferase inhibitor R115777 (Zarnestra; Johnson and Johnson Pharmaceutical Research and Development, Raritan, NJ) in patients with myelodysplastic syndrome (MDS), using doses recommended in a phase I study in relapsed/refractory leukemia. PATIENTS AND METHODS: Patients with MDS were treated with R115777 at doses of 600 mg orally (PO) bid in cycles of 4 weeks of therapy followed by a 2-week rest period. Dose reduction rules for toxicity were applied. RESULTS: Twenty-seven of the 28 patients treated were assessable. Three patients responded (complete remission, n = 2; partial remission, n = 1). Responders included two patients with refractory anemia with excess blasts and one patient with refractory anemia with excess blasts in transformation. Two of the responders had a diploid karyotype and one had multiple cytogenetic abnormalities including monosomy 5 and 7. The starting dose of 600 mg PO bid resulted in side effects (myelosuppression, fatigue, neurotoxicity, rash, or leg pain) necessitating dose reduction (n = 4) or discontinuation of therapy (n = 7) in 11 (41%) of 27 patients during the induction period (12 weeks). Lower doses of 300 mg PO bid were well tolerated. All responses occurred in patients who had been reduced to this dose level during the initial two cycles. CONCLUSION: This study suggests that R115777 has modest activity in MDS patients, but that, in this patient population, 4 weeks of daily doses of 600 mg PO bid is not tolerated. Further exploration of the optimal dose/schedule and correlation with biologic end points are warranted.

Aged↗
PubMed2004

Modulation of angiogenesis in patients with myelodysplastic syndrome.

Current investigations have revealed that angiogenesis plays a role in the pathogenesis of high-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia, and in the mechanisms of disease progression. Secretion of cytokines and growth factors modulates angiogenesis in the marrow leading to increased vascularity and sustenance of the clonal population. For high-risk MDS patients older than 60 years who are not eligible for aggressive chemotherapy or stem cell transplant, there are few therapeutic options other than supportive treatment. Recent delineation of the pathobiology of MDS has resulted in the development of new agents and treatment modalities that impact on these mechanisms. One of the features of bone marrow pathology is the presence of new vessels, which appear to sustain growth and the hypercellularity of the marrow. Blocking angiogenesis may reduce the microvessel density of the marrow, cellularity, and disease progression. Angiogenesis can be targeted by inhibition of vascular endothelial growth factor (VEGF), which modulates new vessel growth, by the use of antibodies aimed at VEGF and its receptors, as well as receptor tyrosine kinases that block VEGF signaling. Other agents include inhibitors of farnesyl transferase and protein kinase C, which affect upstream modulators of growth factors and their receptor interactions; matrix metalloproteinases, which disrupt matrices and adhesion function promoting vessel growth; and other inhibitors with broader function, such as endostatin, thalidomide, and related analogues.

Angiogenesis Inhibitors↗
PubMed2004

Expression of CD2 in acute promyelocytic leukemia correlates with short form of PML-RARalpha transcripts and poorer prognosis.

We studied the immunophenotype of 100 cases of acute promyelocytic leukemia (APL) with cytogenetic evidence of t(15;17)(q22;q21), 72 hypergranular (M3) and 28 microgranular (M3v), and correlated the results with molecular and clinical features. Most neoplasms (75/100 [75%]) had a typical immunophenotype: CD13+CD33+CD34-HLA-DR-. CD64, CD2, CD34, and HLA-DR were expressed in 27% (24/88), 23% (22/94), 21% (21/100), and 9% (9/98), respectively. CD34 expression was restricted to M3v; HLA-DR and CD2 were expressed more often in M3v than in M3 (P < .001). PML-RARalpha fusion transcripts were detected by reverse transcriptase-polymerase chain reaction in all 70 patients assessed. The short form of PML-RARalpha transcripts was found more frequently in M3v (P < .002) and CD2+ APL (P < .0001) than in M3 and CD2- APL, respectively. The median follow-up was 128 weeks. CD2+ APL was associated significantly with leukocytosis (P = .004), shorter complete remission duration (P = .03), and a trend toward shorter overall survival (P = .07) than CD2- APL. Overall survival for M3v vs M3 (P = .68) and short vs long transcripts (P = .21) was not significantly different. Immunophenotyping is useful for predicting the biologic and clinical behavior of APL.

Adolescent↗
PubMed2003

Revised recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia.

An International Working Group met to revise the diagnostic and response criteria for acute myelogenous leukemia originally published in 1990, as well as to provide definitions of outcomes and reporting standards to improve interpretability of data and comparisons among trials. Since the original publication, there have been major advances in our understanding of the biology and molecular genetics of acute leukemia that are clinically relevant and warrant incorporation into response definitions. Differences from the 1990 recommendations included a category of leukemia-free state, new criteria for complete remission, including cytogenetic and molecular remissions and remission duration. Storage of viable blasts for correlative studies is important for future progress in the therapy of these disorders.

Clinical Trials as Topic↗