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Biomedical subjects

Elihu H Estey

Publications and source records attributed to Elihu H Estey.

At least 37 records · Page 2Linked to original sources
PubMed2003

PML-RARalpha is associated with leptin-receptor induction: the role of mesenchymal stem cell-derived adipocytes in APL cell survival.

Leptin is secreted by bone marrow (BM) adipocytes and stromal cells and was shown to stimulate myeloid proliferation. We here report that primary acute promyelocytic leukemia (APL) cells express high levels of the leptin-receptor (OB-R) long isoform. In cells with regulated promyelocytic leukemia-retinoic acid receptor (PML-RARalpha) expression, inducing PML-RARalpha was found to increase OB-R levels. We then investigated the effects of leptin produced by BM adipocytes on APL cells using a coculture system with mesenchymal stem cell (MSC)-derived adipocytes. In PML-RARalpha-expressing cells, all-trans retinoic acid (ATRA)- and doxorubicin-induced apoptosis were significantly reduced by coculture with adipocyte-differentiated MSCs. This antiapoptotic effect required direct cell-to-cell interactions, was associated with phosphorylation of signal transducer and activator of transcription-3 (STAT3) and mitogen-activated protein kinase (MAPK), and was reduced by blocking OB-R. This report provides a mechanistic basis for the BM adipocyte-leukemia cell interaction and suggests that OB-R receptor blockade may have therapeutic use in APL.

Adipocytes↗
PubMed2003

The clinical significance of soluble CD86 levels in patients with acute myeloid leukemia and myelodysplastic syndrome.

BACKGROUND: Levels of the soluble form of CD86 (sCD86) are elevated in a proportion of patients with leukemia. Although it is a potential modulator of antitumor responses, the significance of sCD86 in patients with hematologic malignancies is unknown. METHODS: The authors evaluated sCD86 levels by enzyme-linked immunosorbent assay in patients with acute myeloid leukemia (AML) (n = 57 patients) and patients with myelodysplastic syndrome (MDS) (n = 40 patients) and analyzed the relation between sCD86 levels and various clinical parameters. RESULTS: Levels of sCD86 were elevated (> 2.32 ng/mL) relative to normal donors (0.22-2.32 ng/mL; n = 51 patients) in 25% of patients with AML and in 27% of patients with MDS. Patients with AML who had elevated sCD86 levels had significantly lower complete remission (CR) rates compared with patients with AML who had normal sCD86 levels. In multivariate analysis using sCD86 as a continuous variable and including the interaction of age and sCD86 as a variable, sCD86 was a significant prognostic factor (P = 0.014) independent of cytogenetics. Further analysis demonstrated that, in patients with AML age 60 years and younger, but not in patients older than 60 years, elevated sCD86 levels were associated with significantly shorter survival (P = 0.04). There was no correlation between sCD86 levels and CR rates or survival in patients with MDS. CONCLUSIONS: The presence in patients with AML of elevated levels of circulating sCD86 were associated with lower CR rates and poor survival. The prognostic significance of sCD86 was independent of cytogenetics but was modulated by age, in that it was independently significant only in younger patients. The results suggest that sCD86 may play a role in modulating immune responses associated with the progression of AML.

Adolescent↗
PubMed2003

Reduced-intensity conditioning for unrelated donor hematopoietic stem cell transplantation as treatment for myeloid malignancies in patients older than 55 years.

Hematopoietic stem cell transplantation from unrelated donors is an effective treatment for myeloid malignancies, but its use is usually restricted to young patients without comorbidities. The development of reduced-intensity preparative regimens has allowed the extension of this form of treatment to older and medically infirm patients. We assessed the outcomes of patients older than 54 years who received unrelated donor transplants for the treatment of myeloid malignancies in our institution. There were 29 patients (median age, 59 years) with advanced acute myeloid leukemia (n = 13), myelodysplastic syndrome (n = 7), and chronic myeloid leukemia (n = 9) included. With a median follow-up of 27 months, the probability of overall and event-free survival, and nonrelapse mortality at one year were 44%, 37%, and 55%, respectively. Grades II to IV acute graft-versus-host disease (GVHD) occurred in 41% of patients and chronic GVHD developed in 63% of patients surviving more than 100 days. Of the 11 survivors, 9 were interviewed and reported good quality of life after transplantation using the Functional Assessment of Cancer Therapy-Bone Marrow Transplant Scale (FACT-BMT) questionnaire, with high scores in all dimensions. Unrelated donor transplantation is a treatment option for older patients with myeloid malignancies. The results in this cohort of patients are comparable with those reported in younger patients with similarly advanced disease.

Age Factors↗
PubMed2003

Effect of circulating blasts at time of complete remission on subsequent relapse-free survival time in newly diagnosed AML.

Standardized criteria for complete remission (CR) in acute myeloblastic leukemia (AML) require the absence of peripheral blood blasts (PBBs). However, MD Anderson (MDA) criteria for CR (CR-MDA), although including the other requirements for CR, have not included the PBB count. We exploit this difference to assess the effect of PBBs at the time of CR-MDA on relapse-free survival (RFS) time. Eighty percent of the 533 patients with newly diagnosed AML or refractory anemia with excess of blasts (RAEB) entering CR-MDA from 1995 to 2000 had no PBBs at time of CR-MDA. Ninety-three percent of the remaining patients, who thus had CR-MDA but not standard CR, had 1% to 5% PBBs at this time. Multivariate analyses, using both conventional and Bayesian approaches, indicated that PBBs had no effect on RFS. For all patients and for the subgroups given and not given granulocyte colony-stimulating factor (G-CSF), the 95% credible interval for the relative risk of failure in the PBB group was nearly centered at 1.0. Thus, our data do not support use of PBBs in defining CR in newly diagnosed AML.

Anemia, Refractory, with Excess of Blasts↗
PubMed2003

Contribution of beta-2 microglobulin levels to the prognostic stratification of survival in patients with myelodysplastic syndrome (MDS).

Prospective analysis of the importance of the plasma levels of beta-2 microglobulin (B2M) in 553 patients with myelodysplastic syndrome (MDS) found that B2M is an independent prognostic variable for survival with weighted significance second only to the karyotype. The incorporation of the B2M covariate into risk assessment of MDS patients added significantly to the power of the IPSS to stratify MDS patients into risk categories. Our results further document that the 2 objectively measured covariates that display the highest power to predict survival, that is, karyotype and B2M, can alone be used for risk stratification. While the results must be verified in an independent and comparable population, our data strongly recommend routine measurement of B2M in patients with MDS.

Female↗
PubMed2003

Increased apoptosis in bone marrow B lymphocytes but not T lymphocytes in myelodysplastic syndrome.

The hallmark of myelodysplastic syndrome (MDS) is enhanced apoptosis in myeloid, erythroid, and megakaryocytic cells in the bone marrow leading to ineffective hematopoiesis. Recent studies suggested that immunological and microenvironmental factors play a role in the pathophysiology of this disease. We report a significant increase in apoptosis in bone marrow B lymphocytes in MDS as compared to that found in acute myeloid leukemia and healthy controls. Furthermore, we demonstrate that patients with refractory anemia with excess blasts in transformation (RAEB-T) had apoptosis levels in lymphocytes similar to those seen in other subtypes of MDS. Our findings suggest that the alterations in B lymphocytes in the form of increased apoptosis can be seen in MDS and support the concept that immune modulation plays a role in the pathophysiology of MDS.

Apoptosis↗
PubMed2003

Adaptive randomized study of idarubicin and cytarabine versus troxacitabine and cytarabine versus troxacitabine and idarubicin in untreated patients 50 years or older with adverse karyotype acute myeloid leukemia.

PURPOSE: Troxacitabine has activity in refractory myeloid leukemia, either as a single agent or when combined with cytarabine (ara-C) or with idarubicin. A prospective, randomized study was conducted in patients aged 50 years or older with untreated, adverse karyotype, acute myeloid leukemia (AML) to assess troxacitabine-based regimes as induction therapy. PATIENTS AND METHODS: Patients were randomized to receive idarubicin and ara-C (IA) versus troxacitabine and ara-C (TA) versus troxacitabine and idarubicin (TI). A Bayesian design was used to adaptively randomly assign patients to treatment. Thus, although there was initially an equal chance for randomization to IA, TA, or TI, treatment arms with a higher success rate progressively received a greater proportion of patients. RESULTS: Thirty-four patients were treated. Randomization to TI stopped after five patients and randomization to TA stopped after 11 patients. Defining success as complete remission (CR) that occurred within 49 days of starting treatment, success rates were 55% (10 of 18 patients) with IA, 27% (three of 11 patients) with TA, and 0% (zero of five patients) with TI. Because three CRs occurred after day 49, final CR rates were 55% (10 of 18 patients) with IA, 45% (five of 11 patients) with TA, and 20% (one of five patients) with TI. The probability that TA was inferior to IA was 70%, with a 5% probability that TA would have a 20% higher CR rate than IA. Survival was equivalent with all three regimens. CONCLUSION: Neither troxacitabine combination was superior to IA in elderly patients with previously untreated adverse karyotype AML.

Acute Disease↗
PubMed2003

Randomized phase I/II study of troxacitabine combined with cytarabine, idarubicin, or topotecan in patients with refractory myeloid leukemias.

PURPOSE: Troxacitabine has significant single-agent activity. This study was conducted to define the dose-limiting toxicities (DLTs) of its combination with cytarabine (ara-C), idarubicin, or topotecan. PATIENTS AND METHODS: Patients with refractory acute myeloid leukemia (AML), advanced myelodysplastic syndromes (MDS), or chronic myelogenous leukemia in blastic phase (CML-BP) were initially randomly assigned to receive troxacitabine 5.0 mg/m(2) by intravenous (IV) infusion over 30 minutes on days 1 to 5 with ara-C 1.0 g/m(2)/d IV [DOSAGE ERROR CORRECTED] over 2 hours on days 1 to 5, idarubicin 12 mg/m(2) by 5 minute IV infusion on days 1 to 3, or topotecan 1.0 mg/m(2) as an continuous IV infusion on days 1 to 5. Doses were then adjusted to define DLT for each combination. RESULTS: Eighty-seven patients (68 AML, eight MDS, 11 CML-BP) were treated. DLTs were hepatic transaminitis, hyperbilirubinemia, and hand foot syndrome (HFS) on the troxacitabine plus ara-C combination. The recommended phase II doses were 6 mg/m(2) once a day for 5 days and 1.0g/m(2) once a day for 5 days, respectively. DLTs were diarrhea, rash, and mucositis on the troxacitabine plus topotecan combination. The recommended phase II doses were 4 mg/m(2) once a day for 5 days and 0.75 mg/m(2) once a day for 5 days, respectively. DLTs were HFS, rash, and mucositis on the troxacitabine plus idarubicin combination. The recommended phase II doses were 4 mg/m(2) once a day for 5 days and 9 mg/m(2) once a day for 3 days, respectively. Among 74 evaluable patients with AML or MDS, 10 (13%) achieved complete remission and four (5%) had hematologic improvement. Two of 11 (18%) evaluable patients with CML-BP returned to chronic phase. CONCLUSION: Troxacitabine-based combinations had significant antileukemic activity.

Adolescent↗
PubMed2003

New designs for phase 2 clinical trials.

Conventional phase 2 clinical trials are typically single-arm experiments, with outcome characterized by one binary "response" variable. Clinical investigators are poorly served by such conventional methodology. We contend that phase 2 trials are inherently comparative, with the results of the comparison determining whether to conduct a subsequent phase 3 trial. When different treatments are studied in separate single-arm trials, actual differences between response rates associated with the treatments, "treatment effects," are confounded with differences between the trials, "trial effects." Thus, it is impossible to estimate either effect separately. Consequently, when the results of separate single-arm trials of different treatments are compared, an apparent treatment difference may be due to a trial effect. Conversely, the apparent absence of a treatment effect may be due to an actual treatment effect being cancelled out by a trial effect. Because selection involves comparison, single-arm phase 2 trials thus fail to provide a reliable means for selecting which therapies to investigate in phase 3. Moreover, reducing complex clinical phenomena, including both adverse and desirable events, to a single outcome wastes important information. Consequently, conventional phase 2 designs are inefficient and unreliable. Given the limited number of patients available for phase 2 trials and the increasing number of new therapies that must be evaluated, it is critically important to conduct these trials efficiently. These concerns motivated the development of a general paradigm for randomized selection trials evaluating several therapies based on multiple outcomes. Three illustrative applications of trials using this approach are presented.

Acute Disease↗
PubMed2003

Treatment options for relapsed acute promyelocytic leukaemia.

Modern molecular technology makes it possible to detect minimal residual acute promyelocytic leukaemia (APL) when the marrow remains in complete remission (CR). Thus, an important question, and the first to be discussed, is whether patients should be treated at molecular relapse, rather than only at haematological relapse. The second question to be addressed is when the various options for treatment of relapsed APL-i.e. all-trans retinoic acid (ATRA) and anthracyclines, arsenic trioxide (ATO), gemtuzumab ozogamycin (GO, 'mylotarg'), and allogeneic or autologous stem cell transplant-should be used. We suggest that patients with relapsed APL have different prognoses and that, accordingly, they should not all be treated identically. We note the significance of extramedullary relapse. We conclude with a summary of treatment recommendations and a discussion of new therapies that might be useful in the future.

Antineoplastic Agents↗
PubMed2003

Current challenges in therapy of myelodysplastic syndromes.

The International Prognostic Scoring System (or, more conveniently, the marrow blast percentage) can be used to divide patients with myelodysplasia into those with better (International Prognostic Scoring System low/ intermediate-1, or <10% blasts) and worse (International Prognostic Scoring System intermediate-2/high, or >10% blasts) prognoses. There is no treatment known to produce responses in the great majority of patients in either group. Hence, most patients should be considered for clinical trials. Exceptions are cases with low serum erythropoietin levels or low marrow cellularity; such cases may benefit from erythropoietin with or without granulocyte colony-stimulating factor or antithymocyte globulin, respectively. A wide variety of new agents are in clinical trial. These can be grouped into biologic or targeted, therapies, acute myelogenous leukemia-type chemotherapy, and allogeneic stem cell transplants. In general, competing risk-to-benefit ratios and consideration of natural histories suggest that patients with a better prognosis should receive biologic therapies first, with transplant reserved until failure. In higher-risk patients, particularly those who are relatively young or have a normal karyotype, acute myelogenous leukemia-type chemotherapy or transplant should be considered earlier in the course. The advent of nonmyeloablative (mini) transplant protocols has extended to 70 to 75 years the age at which transplantation can be performed, although the efficacy of such protocols is unknown. Current data do not permit recommendation of specific regimens in patients with a better or worse prognosis; rather, emphasis should be placed on entry into a clinical trial Finally, because other causes of cytopenias are more treatable, the diagnosis of myelodysplastic syndrome should depend on more than the presence of dysplasia, unless the dysplasia is very severe.

Algorithms↗
PubMed2003

Intravenous corticosteroids to reduce gemtuzumab ozogamicin infusion reactions.

OBJECTIVE: To assess whether the addition of a brief course of intravenous corticosteroids reduces the incidence of infusion-related adverse events associated with gemtuzumab ozogamicin (GO) administration. METHODS: One hundred forty-three sequential patients received GO-based therapy for refractory myeloid leukemias: 110 patients received the standard regimen of acetaminophen 650 mg orally with diphenhydramine 50 mg intravenously and 33 patients received the same premedications with methylprednisolone sodium succinate 50 mg intravenous piggyback (IVPB) prior to infusion and repeated 1 hour into the infusion. RESULTS: Of 110 patients who received GO with standard premedications alone, 32 (29%) had grade 2 or above infusion-related adverse events. In 33 patients who received these premedications with methylprednisolone 50 mg IVPB prior to infusion and repeated 1 hour into the infusion, only 1 (3%) experienced any infusion-related adverse events (p = 0.0009, 95% CI 0.16 to 0.36). There was no significant difference between the patient cohorts in terms of hepatotoxicity, rate of development of hepatic venoocclusive disease, response rates, or infectious complications. CONCLUSIONS: A brief course of intravenous corticosteroids significantly reduces the incidence of GO infusion-related adverse events.

Acetaminophen↗
PubMed2003

Independent prognostic significance of day 21 cytogenetic findings in newly-diagnosed acute myeloid leukemia or refractory anemia with excess blasts.

BACKGROUND AND OBJECTIVES: We investigated whether cytogenetic findings (CG) on day 21 (D21) of the first course of chemotherapy predicted subsequent outcome in patients who presented with CG abnormalities. DESIGN AND METHODS: D21 CG analysis was performed in 197 patients. RESULTS: Nineteen percent of the patients had exclusively abnormal metaphases (AA), 31% had only normal metaphases (NN), 39% had normal and abnormal metaphases (AN), and 11% had insufficient metaphases (0/0) on D21. A complete response was achieved in 79% of patients with NN, 60% with AN, 27% of those with AA, and 32% of those with 0/0. INTERPRETATIONS AND CONCLUSIONS: Disease-free survival in CR was longest in patients who had > or =1 normal metaphase on D21, with this finding being independent of D21 marrow and initial CG results. D21 CG can be used in therapeutic decision-making.

Acute Disease↗
PubMed2003

Comparative efficacy and safety of gemtuzumab ozogamicin monotherapy and high-dose cytarabine combination therapy in patients with acute myeloid leukemia in first relapse.

Gemtuzumab ozogamicin was recently approved in the United States for the treatment of older patients with CD33-positive acute myeloid leukemia (AML) in first relapse. However, the lack of randomized clinical trials makes it so difficult to determine which patients are best suited for this compared with other treatment regimens. Results for 128 patients given gemtuzumab ozogamicin in phase II trials were compared with those for 128 patients given high-dose cytarabine (HDAC) combination therapy in different trials Multivariate logistic regression was used to analyze age, duration of first complete remission (CR1), and cytogenetics for potential differences between the groups. rare of overall remission )combined complete remission [CR] plus CR with incomplete platelet recovery [CRp]) following treatment with gemtuzumab ozogamicin or HDAC therapy were 38% and 41%, respectively. Gemtuzumab ozogamicin treatment was associated with a higher overall remission rate compared with HDAC treatment if CR1 duration was 3-10.5 months. In contrast, HDAC treatment was associated with a higher overall remission rate than gemtuzumab ozogamicin treatment if CR1 duration was >19 months. If CR1 duration was between 10.5 and 19 months, the differences in treatment responses were not statistically significant. Thee results reflect the much stronger treatment than with gemtuzumab ozogamicin treatment. Early death (occurring within the first 6 weeks of therapy) was less likely in patients <45 years of age after ADAC and was less likely in patients >75 years of age after gemtuzumab ozogamicin treatment. These data support the recommended use of gemtuzumab ozogamicin as monotherapy in older patients with AML in first relapse, but caution against this use in patients, particularly younger ones, with a long duration of CR1.

Acute Disease↗
PubMed2002

Plasma vascular endothelial growth factor levels have prognostic significance in patients with acute myeloid leukemia but not in patients with myelodysplastic syndromes.

BACKGROUND: Vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) are positive regulators of angiogenesis. Increased levels in urine, serum, plasma, or malignant tissue have been associated with an adverse prognosis in patients with solid tumors. METHODS: The authors used an enzyme-linked immunosorbent assay to measure VEGF and bFGF levels in plasma samples from 99 patients with previously untreated myelodysplastic syndromes (MDS) (n = 41 patients; 42%) or acute myeloid leukemia (AML) (n = 58 patients; 58%) and compared the results with the results from a group of normal control participants. RESULTS: Increased expression levels of VEGF and bFGF were found in the plasma from patients with AML and MDS (P < 0.01) compared with the levels found in the control group. Plasma levels of VEGF in patients with AML or MDS were similar (median, 30.63 pg/mL and 34.41 pg/mL, respectively). There was no significant difference in bFGF levels between patients with AML and patients with MDS (median, 6.38 pg/mL and 6.98 pg/mL, respectively). Elevated levels of VEGF were associated with reduced survival (P = 0.02) in patients with AML as well as lower complete remission (CR) rates (P = 0.004). Elevated VEGF levels were not associated with reduced remission duration (CRD) in patients with AML. There was no correlation between VEGF levels and survival, CRD, or CR rates in patients with MDS. There was no correlation between bFGF levels and CR rates or survival in patients with either AML or MDS. CONCLUSIONS: Plasma VEGF levels have prognostic significance in patients with AML. The lack of clinical relevance of VEGF levels in patients with MDS suggests some biologic difference between AML and MDS.

Acute Disease↗
PubMed2002

Myelodysplastic syndrome is not merely "preleukemia".

Myelodysplastic syndrome (MDS) is a disease characterized by ineffective hematopoiesis. There are significant biologic and clinical differences between MDS and acute myeloid leukemia (AML). We studied a cohort of 802 patients, 279 (35%) with newly diagnosed MDS and 523 (65%) with newly diagnosed AML, and compared clinical and biologic characteristics of the 2 groups. Complete clinical and cytogenetic data were available on all patients, and a subgroup of patients was studied for apoptosis, angiogenesis, proliferation, and growth factors. Our results demonstrate that MDS is a discrete entity that is different from AML and is characterized primarily by increased apoptosis in early and mature hematopoietic cells. Using cell sorting and loss of heterozygosity, we demonstrate that the leukemic cells from MDS patients are capable of differentiation into mature myeloid cells and monocytes. We also demonstrate that there is a significant overlap between AML and MDS when MDS is defined on the basis of an arbitrary percentage of blasts of 20% or 30%. These data suggest that despite similarities between AML and MDS in their responses to treatment and outcomes, MDS is biologically and clinically different from AML and should not be considered an early phase of AML. The data indicate that MDS must be better defined on the basis of its biology rather than the percentage of blasts; further, the data suggest that there is a need to develop therapeutic approaches that specifically address the biologic abnormalities of MDS.

Acute Disease↗