Search PubMed⌕ Search

Biomedical subjects

E H Estey

Publications and source records attributed to E H Estey.

At least 73 records · Page 4Linked to original sources
PubMed1995

Role of suramin as an IL-1 inhibitor in suppression of acute myelogenous leukemia progenitor proliferation.

Interleukin-1 (IL-1) modulates both autocrine and paracrine growth-stimulatory mechanisms of acute myelogenous leukemia (AML) cell proliferation. Recent studies show that blocking the interaction between IL-1 and its receptor may suppress this proliferation. Because suramin, a polysulfonated naphthylurea originally described as an antitrypanosomal agent, was found to inhibit the binding of several growth factors to their receptor, we tested its effect on AML progenitor proliferation. We first examined the effect of suramin on murine EL-4.6.1 cells that express type I IL-1 receptors and found that suramin inhibited the binding of IL-1 to its receptor. We then tested the effect of suramin on AML progenitors using bone marrow samples from 17 patients with AML. In all experiments, suramin inhibited AML blast proliferation in a dose-dependent fashion at concentrations ranging from 30 to 240 microM. IL-1 beta (100 U/mL) partially reversed this inhibitory effect. Suramin also inhibited normal early and mature hematopoietic progenitors, as assessed by both the delta assay and the mixed colony culture assay; however, at the same concentration, suramin suppressed the colony growth of colony-forming units granulocyte-macrophage (CFU-GM) by only 45% compared with an 89% suppression of AML progenitors. IL-1 beta did not negate this inhibitory effect, which suggests that another growth inhibitory mechanism might be operative. Our data suggest that suramin may inhibit AML progenitor proliferation by blocking the interaction of IL-1 and its receptor; therefore, further studies are warranted to evaluate suramin's therapeutic potential in patients with AML.

Adult↗
PubMed1995

Prognostic value of residual normal metaphases in acute myelogenous leukemia patients presenting with abnormal karyotype.

Two hundred and forty-four untreated acute myelogenous leukemia (AML) patients with unfavorable karyotypes and 109 others with favorable aneuploid karyotypes were used to evaluate the prognostic significance of having both normal and abnormal metaphases (AN) vs only abnormal metaphases (AA) at AML presentation. The AA and AN groups were similar with respect to known prognostic variables. Among patients with unfavorable karyotypes (-5, 5q-, -7, 7q-, and +8), the AN group had a significantly higher complete remission (CR) rate (46 vs 31%, P = 0.02), and a longer CR duration (P = 0.02) and survival (P = 0.026) than the AA group. The number of patients with other unfavorable karyotypes, such as t(11q23), were too small to evaluate properly. Among those with favorable karyotypes (inv(16) and t(8;21)), on the other hand, both the AN and AA group had similar CR rate, CR duration, and survival. Similarly, in patients with t(15;17), CR duration of the AN and AA groups were similar. These data suggest that, among patients with abnormal karyotypes, residual normal metaphases are associated with a higher CR rate, CR duration and survival, only in patients with unfavourable karyotypes, but not in those with favorable karyotypes.

Adult↗
PubMed1995

Response to interferon-alpha in patients with hairy cell leukemia relapsing after treatment with 2-chlorodeoxyadenosine.

2-Chlorodeoxyadenosine (2-CdA) has recently established itself as an extremely effective therapy for patients with hairy cell leukemia. To date, the issue of how to treat patients relapsing after 2-CdA has not been adequately addressed. In our initial study, 41 of 46 patients achieved an objective response (complete or partial remission). The only persistent toxicity associated with this agent appears to be significant suppression of CD4+ lymphocyte counts, albeit without evidence of clinical sequelae at a median follow-up of 30 months (range, 7-43). Eight patients have developed recurrent disease 3-23 months (median, 16 months) after 2-CdA. Because of progressive cytopenias, three of these patients were treated with interferon-alpha (IFN-alpha) (3 x 10(6) units subcutaneously three times per week), commencing 2, 9 and 16 months after the documentation of relapse. All three patients have shown an objective response with reduction of marrow hairy cells and amelioration of neutropenia and thrombocytopenia (two patients, complete remission; one patient, partial remission). Responses were maintained while on IFN-alpha, but two patients relapsed shortly (3 and 4 months, respectively) after discontinuation of IFN. There was no significant toxicity. Prior to commencing IFN-alpha, 22-36 months after 2-CdA, these patients' absolute CD4+ counts were suppressed (mean 211/microliters, s.d. +/- 85/microliters), but have not significantly changed after 10, 11 and 18 months of IFN-alpha therapy (mean 225/microliters, s.d. +/- 93/microliters). These results suggest that in hairy cell leukemia patients relapsing after 2-CdA, IFN-alpha may be a reasonable therapeutic option, especially if persistent CD4+ lymphocytopenia is present.

Adult↗
PubMed1995

High remission rate, short remission duration in patients with refractory anemia with excess blasts (RAEB) in transformation (RAEB-t) given acute myelogenous leukemia (AML)-type chemotherapy in combination with granulocyte-CSF (G-CSF).

A study was made to determine CR rate, response duration and survival in patients with RAEB or RAEB-t given AML-type chemotherapy, in particular the newer agents idarubicin and fludarabine. Eighty-five adults (58 RAEB-t, 27 RAEB) received either IA (idarubicin 12 mg/m2 daily on days 1-3, ara-C 1.5 g/m2 daily on days 1-4 CI), FA (fludarabine 30 mg/m2 daily on days 1-5, ara-C 2 g/m2 daily on days 1-5) or FLAG (FA + G-CSF 400 micrograms/m2 daily from day-1 until CR). IA was given exclusively to patients with better prognosis (as assessed by pretreatment karyotype), while FA and FLAG were given first to patients with worse and then to those with better prognosis. In remission, patients received lower doses of the same regimens for 6-12 months. The 85 patients comprise the largest reported series of RAEB or RAEB-t patients given AML-type chemotherapy. Their median age was 61 years, 33% had chromosome 5 or 7 abnormalities (-5/-7), and 55% were treated in laminar air flow rooms. The CR rate was 66%. While rates were highest in younger patients with a normal karyotype, CR rates in excess of 50% were also obtained in patients over age 60 (27/47; 57%) and in patients with -5/-7 (17/29; 59%). In 11 of the 14 cytogenetically abnormal patients in whom cytogenetic analysis was repeated at the time of CR, only normal metaphases were found. In the remaining 3 the number of abnormal metaphases was substantially reduced. However, the probability of continued CR was low (e.g. 452 +/- 0.08 at 12 months), and the only patients alive in CR beyond two years were patients under age 60 without -5/-7 and with RAEB-t. Survival probability was 0.35 +/- 0.05 at one year. Eight of 56 patients died in CR. While current AML-type chemotherapy can produce higher CR rates than is perhaps usually appreciated, in some patients with RAEB or RAEB-t (e.g. older patients with -5/-7) the brevity of the remissions and the risk entailed suggest that new post-remission therapies are needed to make this approach generally worthwhile.

Adult↗
PubMed1994

2-chlorodeoxyadenosine induces durable remissions and prolonged suppression of CD4+ lymphocyte counts in patients with hairy cell leukemia.

A number of effective treatments are available for patients with hairy cell leukemia (HCL). 2-Chlorodeoxyadenosine (2-CdA) induces more than 80% complete responses, but is associated with profound suppression of CD4+ lymphocyte counts. However, the duration of each is uncertain. We have analyzed a previously reported cohort of 40 patients who had responded to 2-CdA. Eight patients (20%) have relapsed at a median of 16 months (range, 3 to 23 months). The remaining 32 patients were observed for a median of 30 months (range, 7 to 43 months). No patients have died. At 3 years, the actuarial disease-free survival rate is 77% (95% confidence interval, 70% to 84%). The median CD4+ lymphocyte count before therapy was 743/microL (range, 58 to 2,201/microL). The median CD4+ nadir after treatment was 139/microL (range, 25 to 580/microL). There was a single opportunistic infection and no second malignancies observed. Although there was evidence of some improvement in CD4+ lymphocyte counts on sequential testing, CD4+ counts remained significantly lower than baseline (P < .0001) at a median of 23 months after therapy (median, 237/microL; range, 25 to 514/microL), and were also lower than baseline (P < .002) in those patients with more than 1 year of follow-up (median, 27 months; range, 13 to 42 months). The median time to reach an absolute CD4+ lymphocyte count of 365/microL, the lower limit of the normal range, was 40 months. Although responses to 2-CdA are durable in the majority of patients with HCL, the uncertain long-term consequences of the observed CD4+ lymphocytopenia suggest caution in the broad application of this therapy.

CD4-Positive T-Lymphocytes↗
PubMed1994

Acute lymphocytic leukaemia in the elderly: characteristics and outcome with the vincristine-adriamycin-dexamethasone (VAD) regimen.

To analyse the pretreatment characteristics, response to therapy, and overall prognosis of elderly patients with acute lymphocytic leukaemia (ALL), 268 consecutive adults with newly-diagnosed ALL who received the vincristine-adriamycin-dexamethasone (VAD) regimens were reviewed. Pretreatment characteristics, response to VAD therapy, and overall outcome were analysed in patients 60 years or older, and compared to younger patients. Fifty-two patients (19%) were 60 years or older. Compared with younger patients, elderly patients with ALL had a significantly worse performance status at presentation (P < 0.001); higher incidences of FAB L2 morphology (P = 0.03), thrombocytopenia (P < 0.01), hypoalbuminaemia (P < 0.001) and renal dysfunction (P = 0.03); and trends for worse anaemia (P = 0.06) and a higher rate of myeloid markers positivity (P = 0.06). With VAD induction therapy, elderly patients had a lower CR rate than younger patients following two induction courses (CR rate 58% v 82%; P < 0.01), and overall (CR rates 65% v 90%; P < 0.01). The response rate to VAD chemotherapy, however, appeared superior to the 30-35% CR rates reported from other series in elderly ALL patients. The lower CR rate was due to both higher induction mortality (P = 0.02) and more resistant disease (P < 0.01). The long-term CR rate was 20% in elderly patients achieving CR, but the overall survival was poor (< 10% at 3 years). There were strong associations between older age and other poor prognostic features. However, multivariate analyses identified older age to be an independent poor prognostic factor for response to chemotherapy. In summary, elderly patients with ALL have an appreciable CR rate with the VAD regimens. Patients achieving CR may have durable remissions. The myelosuppression-associated mortality in both remission induction and maintenance may be reduced with the addition of growth factors in both treatment phases, and by using standard maintenance therapy without consolidation-intensification phases.

Age Factors↗
PubMed1994

Detection of AML1/ETO fusion transcript as a tool for diagnosing t(8;21) positive acute myelogenous leukemia.

The nonrandom chromosomal translocation t(8;21)(q22;q22) can be found frequently in acute myelogenous leukemia with maturation (AML-M2). The breakpoint of this translocation has been cloned and characterized, and fusion transcript AML1/ETO has been identified. Reverse transcription polymerase chain reaction (RT-PCR) can be used to amplify the breakpoint site of AML1/ETO in t(8;21)-positive AML-M2 patients. The chimeric transcript can be detected in all 16 (100%) t(8;21)-positive AML-M2 patients. In all samples, the size of the amplified DNA fragments and pattern of restriction digest were identical, indicating that the t(8;21) translocation breakpoint occurs within a single intron of the AML1 and ETO genes. Interestingly, this fusion transcript was also detected in one of 13 AML-M2 patients without the t(8;21) translocation, indicating that a masked translocation involving chromosomes 8 and 21, exists in AML. Minimal residual disease was detected by semi-nested RT-PCR in all four patients tested, who had been in complete remission for 12, 15, 34, and 52 months, respectively. These results indicate that RT-PCR amplification of the AML1/ETO fusion transcript is a powerful tool for diagnosing and monitoring minimal residual disease in AML-M2 patients.

Adolescent↗
PubMed1994

Investigation of karyotypic, morphologic and clinical features in patients with acute myeloid leukemia blast cells expressing the neural cell adhesion molecule (CD56).

The mechanisms of extramedullary leukemic infiltration are not well characterized. The cell-surface glycoprotein CD56, which is identical to the neural cell adhesion molecule, may be involved. Using the Leu-19 antibody and flow cytometric methods, the leukemic blasts of 22% (70 of 314) of patients were CD56 positive. This was most common in acute monocytic leukemia (15 of 18, 83%) and in patients with the cytogenetic abnormalities t(8;21) (seven of 13, 54%) and trisomy 8 (nine of 22, 41%). CD56 expression was not associated with extramedullary leukemic infiltration, but was correlated with positivity for CD11b (p < 0.001), CD14 (p < 0.001) and CD19 (p = 0.018). Although associated with morphologic and cytogenetic features, CD56 expression alone cannot account for most instances of tissue infiltration in acute myeloid leukemia (AML).

Adolescent↗
PubMed1994

Cytogenetic evolution following the transformation of myelodysplastic syndrome to acute myelogenous leukemia: implications on the overlap between the two diseases.

Cytogenetic evolution in the myelodysplastic syndrome (MDS) has been associated with an abrupt shift to acute myelogenous leukemia (AML). To investigate the 'evolution' of MDS to AML we compared the karyotypes of MDS patients at presentation and at development of AML. Of 170 patients with MDS who developed AML, 63 had banded karyotypes done at both time points. Fifteen patients had refractory anemia (RA) or RA with ringed sideroblasts (RARS), 27 had RA with excess blasts (RAEB), and 21 had RAEB in transformation (RAEBT). Patients had MDS for at least 12 weeks prior to developing AML. Thirty-one patients received cytotoxic therapy for MDS. Seventeen of 63 patients (27%) acquired a cytogenetic change when they developed AML. This percentage was significantly higher in RA/RARS patients compared to RAEB/RAEBT (53.3 vs. 18.8%, p < 0.01). Age, prior malignancy, cytotoxic therapy for MDS, and time to development of AML did not influence the probability of acquiring a cytogenetic change. The small number of patients did not allow testing for the effect of specific karyotypes on the incidence of cytogenetic change or the effect of this change on AML prognosis. The only recurring cytogenetic change was addition of chromosome 13 which occurred in four of 17 patients who changed. These data suggest that a cytogenetic change may be partly responsible for the transformation of RA/RARS, but not RAEB or RAEBT, to AML. This supports the concept that RAEB, RAEBT, and AML are different manifestations of the same disease, whereas RA/RARS are conditions that predispose to acute leukemia.

Adolescent↗
PubMed1994

Long-term results following treatment of newly-diagnosed acute myelogenous leukemia with continuous-infusion high-dose cytosine arabinoside.

The long-term results in 130 patients with newly diagnosed acute myelogenous leukemia treated with continuous infusion high-dose ara-C (1.5 gm/m2/day x 4 days, CIHDAC) were compared with those in 264 patients treated in previous studies with standard dose ara-C (70-90 mg/m2/d x 7 days) plus either adriamycin (Ad-OAP), or amsacrine (AMSA-OAP). All patients have been followed at least 5 years. Patients in first CR at 5 years (FCR5) treated on protocols prior to CIHDAC had only 5% chance of relapse (median subsequent follow-up of 9 years). Therefore, we considered patients in FCR5 potentially cured. The two groups were similar with respect to known prognostic factors and CR rates. Although remission duration and survival were shorter with CIHDAC than Ad-OAP/AMSA-OAP, the percent of patients potentially cured was similar (10 vs. 15%). Marked differences between regimens were seen in inv(16) and t(15;17) patients. CIHDAC was better for patients with inv(16) with more patients in FCR5 (80 vs. 38%), longer remission duration and survival, and lower incidence of CNS relapse (0 vs. 43%). The Ad-OAP/AMSA-OAP protocols were superior in patients with t(15;17). We also measured steady-state ara-CTP concentrations (ara-CTPss) in 54 CIHDAC-treated patients presenting with high-blast count. While there was no correlation between ara-CTPss and response duration, all five patients in FCR5 in whom ara-CTPss was measured had high concentrations. These data support the concept that patients with AML should be treated differently according to cytogenetics. Inv(16) patients should be treated with high-dose ara-C while t(15;17) should rely more on anthracycline exposure.

Adolescent↗
PubMed1993

A Bayesian strategy for screening cancer treatments prior to phase II clinical evaluation.

We address the problem of selecting a treatment for phase II evaluation when several candidate treatments emerging from phase I testing are available. A pre-phase II Bayesian selection design which randomizes patients among treatments is proposed. The patient group in the trial has prognosis more favourable than that of phase I patients but less favourable than the target group of the subsequent phase II trial. The patient response rate distribution in each treatment arm is continually updated during the trial for comparison with early termination cutoffs, and the best final treatment must satisfy a minimal posterior efficacy criterion. The primary aim is to replace the usual informal treatment selection process with a fair comparison formally based on a combination of prior opinion and clinical data.

Antineoplastic Agents↗
PubMed1993

Advances in therapy for hairy cell leukemia. A review.

BACKGROUND: Hairy cell leukemia (HCL) is a chronic B-cell malignancy, typically seen in middle-aged men, characterized by pancytopenia, splenomegaly, immunologic abnormalities, and morphologically typical neoplastic mononuclear cells in the blood, bone marrow, liver, spleen, and other tissues. Diagnosis is confirmed by demonstration of hairy cells in biopsy specimens from the bone marrow or spleen or in peripheral blood. The natural history of this lymphoproliferative disorder varies. Patients may die early during the initial phase of therapy; others may require no therapy; and for some, splenectomy alone, without further treatment, may suffice for many years. Recently, the nucleosides pentostatin (2'-deoxycoformycin) (DCF) and 2'-chlorodeoxyadenosine (2-CdA) have been shown to produce greater numbers of durable complete remissions with curative potential in patients with HCL. The treatment options, with emphasis on major therapeutic advances with alpha-interferon, DCF, and 2-CdA, are reviewed in this article. METHODS: Studies on HCL published from 1958 to 1992 were reviewed using the Cancerline and Medline retrieval systems and other bibliographies. RESULTS: Management of HCL has changed in the last decade as a result of three new effective agents: alpha-interferon DCF, and 2-CdA. DCF has produced an overall response rate of 86% and a complete remission rate of 62%. 2-CdA has yielded an overall response rate of 95% and a complete remission rate of 82%. Alpha-interferon has given an overall response rate of 82% and a complete remission rate of 8%. Other agents with limited activities include chlorambucil, cyclophosphamide, cytarabine, vincristine, doxorubicin, and zorubicin hydrochloride. The effects of lithium carbonate, immunotherapy, splenic irradiation, androgens, and leukaphoresis are minimal and transient. CONCLUSIONS: Modern management of HCL with 2-CdA and DCF is now potentially curative rather than palliative in some patients; however, the optimal therapeutic approach remains uncertain. Alpha-interferon has been approved by the Food and Drug Administration as the first-line drug therapy, followed by DCF in non-responding patients. 2-CdA remains an experimental therapy, but its higher response rate and ease of administration may make it the first-line treatment of choice. Additional research into the biology of HCL and further clinical trials are needed to determine the optimal treatment strategy for this disorder. Therefore, the best therapeutic approach at the current time is to include patients with HCL in ongoing clinical trials.

2-Chloroadenosine↗
PubMed1993

Expression of unusual immunophenotype combinations in acute myelogenous leukemia.

Immunophenotypes for 272 patients with acute myelogenous leukemia (AML) were analyzed using a panel of 22 antibodies. Numerical evidence for unusual coexpressions (present in normal marrow at < or = 0.1%) of surface markers on > or = 10% of the blast cells was found in 85% of all cases. Asynchronous expression of myeloid differentiation antigens occurred in 70% of the cases. Unusual coexpression of T-lymphoid, B-lymphoid, or natural killer (NK) markers with myeloid markers occurred in 38%, 13%, and 21%, respectively, of all AML cases. Two- and three-color analyses confirmed coexpression in 15 of 15 cases, and indicated that these percentages are an underestimate, because coexpression can be demonstrated in cases without numerical overlap. These data indicate that the unusual coexpression of normal differentiation antigens is a common occurrence in AML. Markers in 12 of 13 patients were similar between presentation and relapse, and in two patients, unusual phenotypes detected at first relapse were shown at second relapse, indicating these immunophenotypes are stable in the majority of AML patients. Significant correlations were found between t(8;21) cytogenetics and coexpression of CD19 with CD15 or CD34, t(9;22) and coexpression of CD19 and CD34, and t(15;17) and coexpression of CD2 and myeloid antigens. Multiparameter fluorescence analysis allows detection of unusual phenotypes when the blast counts are < 5% (classical remission). Analysis of 16 patients in remission indicated the presence of presentation phenotypes in 0.2% to 7.9% of the lymphocyte + blast light scatter region, representing 0.03% to 1.4% of the total nucleated marrow cells. Of the 16 patients with > or = 4 months follow-up after detection of these cells, 6 of 6 patients with > or = 0.2% unusual presentation phenotypic marrow cells have relapsed, while 9 of 10 patients with < 0.2% remain in remission. The detection of cells with the unusual presentation phenotype may reflect residual AML cells, and their increase may predict relapse.

Adult↗
PubMed1993

The prognostic significance of auer rods in myelodysplasia.

The category of refractory anaemia with excess blasts in transformation (RAEBt) of the French-American-British (FAB) classification system comprises a heterogeneous group of patients: those with any combination of 5% or more blood blast cells, more than 20% but no more than 30% marrow blast cells, or the presence of auer rods and 30% or less marrow blast cells. To determine the prognostic significance of auer rods in RAEBt, we classified the 208 patients with RAEBt seen between 1973 and 1992 as (1) those having RAEBt solely on the basis of auer rods (RAEBta, n = 29), (2) those meeting blood or marrow blast criteria for RAEBt and also having auer rods (RAEBtpos, n = 40) or (3) those meeting blood or marrow blast criteria for RAEBt without having auer rods (RAEBtneg, n = 139). The RAEBta group had a higher survival probability than either of the other two groups. Within RAEBta, those patients who, without auer rods, would be considered RAEB by the FAB system (n = 19) had a higher probability of survival than patients with RAEB as conventionally defined. Furthermore, patients with RAEBtpos were more likely to live longer than those with RAEBtneg. The RAEBta, RAEBtpos and RAEBtneg groups were similar with regard to the usual haematologic parameters. However, patients with auer rods were more likely to have a normal karyotype and less likely to have prognostically unfavourable cytogenetic abnormalities. When analysis was performed within cytogenetic groups, the favourable prognostic impact of auer rods was still evident. Similarly, the favourable prognostic significance of auer rods was discernible both among patients who did not receive intensive therapy and those who received induction chemotherapy. The complete remission rate in auer rod positive patients was 77%, compared to 27% in those without auer rods. There were no differences in remission duration. Our results suggest that: (1) patients with auer rods without blood or bone marrow blast criteria for RAEBt should not be grouped with those patients with such criteria, and (2) patients with auer rods and other criteria for RAEBt have a higher complete remission rate following induction therapy of the type frequently reserved for patients with acute myeloid leukaemia.

Adult↗