PubMed Health⌕ Search

Biomedical subjects

E H Estey

Publications and source records attributed to E H Estey.

At least 19 recordsLinked to original sources
PubMed2000

Effect of time to complete remission on subsequent survival and disease-free survival time in AML, RAEB-t, and RAEB.

The authors examined the relationship between the time required to enter complete remission (CR) after a first course of chemotherapy for newly diagnosed acute myeloid leukemia (AML), refractory anemia with excess blasts in transformation (RAEB-t), or refractory anemia with excess blasts (RAEB). They also examined subsequent survival time and disease-free survival time after accounting for cytogenetic status, age, and treatment. The data set consisted of 1101 patients with these diagnoses treated at the M. D. Anderson Cancer Center between 1980 and 1996 for whom outcomes were established after first-course therapy. Of the 1101 patients, 740 (67%) were in CR after this time; 508 of these 740 (69%) have died (80% had disease recurrence before death). The authors used the parametric model of Shen and Thall to estimate, in particular, T(C) (time to CR), T(C,D) (time from CR to death = residual survival after CR), and T(C,R) (residual disease-free survival [DFS] after CR) as functions of the covariates noted above and to estimate the dependence of T(C,D) and T(C,R) on T(C). There was a strong inverse association between T(C) and both T(C,D) and T(C,R) (P <.001 for both) that was independent of cytogenetic status, age, or treatment. The residual survival time of patients who required >50 days to enter CR was closer to the residual survival time of resistant patients than to that of patients known to be in CR within approximately 30 days of the start of treatment. Time to CR is an independent predictor of residual survival and disease-free survival in patients with newly diagnosed AML who achieve CR after 1 course of chemotherapy. (Blood. 2000;95:72-77)

Age Factors↗
PubMed1999

Phenylarsine oxide blocks interleukin-1beta-induced activation of the nuclear transcription factor NF-kappaB, inhibits proliferation, and induces apoptosis of acute myelogenous leukemia cells.

Arsenic compounds have recently been shown to induce high rates of complete remission in patients with acute promyelocytic leukemia (APL). One of these compounds, As(2)O(3), induces apoptosis in APL cells via a mechanism independent of the retinoic acid pathway. To test the hypothesis that arsenic compounds may be effective against other forms of acute myelogenous leukemia (AML), we studied the membrane-permeable arsenic compound phenylarsine oxide (PAO). Because interleukin-1beta (IL-1beta) plays a key role in AML cell proliferation, we first tested the effect of PAO on OCIM2 and OCI/AML3 AML cell lines, both of which produce IL-1beta and proliferate in response to it. We found that PAO inhibited the proliferation of both OCIM2 and OCI/AML3 cells in a dose-dependent fashion (0.01 to 0.1 micromol/L) and that IL-1beta partially reversed this inhibitory effect. We then measured IL-1beta levels in these cells by using an enzyme-linked immunosorbent assay and Western immunoblotting and found that PAO almost completely abolished the production of IL-1beta in these AML cells, whereas it did not affect the production of IL-1 receptor antagonist. Because PAO inhibits activation of the transcription factor NF-kappaB and because NF-kappaB modulates an array of signals controlling cellular survival, proliferation, and cytokine production, we also studied the effect of PAO on NF-kappaB activation in AML cells and found that PAO suppressed the IL-1beta-induced activation of NF-kappaB. Because inhibition of NF-kappaB may result in cellular apoptosis, we also tested whether PAO may induce apoptotic cell death in AML cells. We found that PAO induced apoptosis in OCIM2 cells through activation of the cystein protease caspase 3 and subsequent cleavage of its substrate, the DNA repair enzyme poly (ADP-ribose) polymerase. The PAO-induced apoptosis was caspase dependent, because it was completely blocked by the caspase inhibitor Z-DEVD-FMK. Finally, we tested the effect of PAO on fresh AML marrow cells from 7 patients with newly diagnosed AML and found that PAO suppressed AML colony-forming cell proliferation in a dose-dependent fashion. Taken together, our data showing that PAO is an effective in vitro inhibitor of AML cells suggest that this compound may have a role in future therapies for AML.

Acute Disease↗
PubMed1999

Molecular remissions induced by liposomal-encapsulated all-trans retinoic acid in newly diagnosed acute promyelocytic leukemia.

All-trans retinoic acid administered orally (oral ATRA) may not regularly lead to either molecular complete remissions (CRs) or prolonged hematologic CRs (HCR) unless combined with chemotherapy. Because serum tretinoin concentrations are higher, and maintained longer, after use of liposomal-encapsulated ATRA (lipoATRA) rather than oral ATRA, we investigated lipoATRA monotherapy in newly diagnosed acute promyelocytic leukemia (APL). Patients received lipoATRA 90 mg/m(2) every other day for remission induction. The same dose was given 3 times a week until 9 months had elapsed from HCR date. Treatment then stopped. Chemotherapy (idarubicin 12 mg/m(2) daily days 1-2 for 2 courses) was to be added only if 2 polymerase chain reaction (PCR) tests, performed 2 weeks apart, were positive at 3, 6, or 9 months from HCR date. The sensitivity level of the PCR was 10(-4). We treated 18 patients (median age, 54 years; median white blood cell [WBC] count 4,500/microL). The HCR rate was 12/18 (67%, 95% confidence interval [CI], 41% to 87%). This rate was similar to that we observed in a previous study using oral ATRA + idarubicin. Nine of 10 patients studied at HCR date were PCR-positive. Subsequently, however, overall (+/- idarubicin) rates of PCR positivity were 0/12 at 3 months, 1/10 at 6 months, 1/7 at 9 and 12 months, and 0/4 at 15 to 17 months. Idarubicin has been added in 3 patients, with this addition occurring at 6 months in 2 patients and at 9 months in 1 patient. Among patients who had not received idarubicin when the PCR was evaluated, 0 of 12 were PCR-positive at 3 months, 1 of 10 was positive at 6 months, 1 of 6 was positive at 9 months, 0 of 4 were positive at 12 months, and 0 of 3 were positive at 15 to 17 months. Morphologic APL has recurred in 1 patient, with a median follow-up time of 13 months in the 11 patients remaining in first CR. The median follow-up time is 91/2 months (range, 3 to 17) in the 9 patients who have received only lipoATRA and who remain PCR-negative and in first CR. Our data suggest that lipoATRA is an effective means of producing molecular CR in newly diagnosed APL.

Administration, Oral↗
PubMed1999

Accrual strategies for phase I trials with delayed patient outcome.

Phase I dose-finding trials typically are conducted using adaptive rules that select dose levels for successive patient cohorts based on the outcomes of patients treated previously in the trial. When patient outcome cannot be observed immediately after treatment, the problem arises of how to deal with new patients while waiting to observe the current patient cohort's outcomes. We consider two alternative approaches to this problem in the context of a phase I trial conducted using the continual reassessment method. With the first approach, a patient requiring treatment before the next cohort opens is treated off protocol with standard therapy, and otherwise waits until the next cohort opens. The second approach treats each patient immediately upon arrival at the dose recommended based on currently available data. We compare these two approaches by simulation under varying dose--toxicity curves, accrual rates, cohort sizes and early stopping rules. We evaluate patient waiting time, trial duration, number of patients treated off protocol and the probabilities of toxicity and of selecting the correct dose. We also study three strategies for assigning patients to trials when two or more phase I trials may be ongoing simultaneously. Based on our results, we provide practical guidelines for deciding among these approaches and strategies in a given clinical setting.

Antineoplastic Agents↗
PubMed1999

Randomized phase II study of fludarabine + cytosine arabinoside + idarubicin +/- all-trans retinoic acid +/- granulocyte colony-stimulating factor in poor prognosis newly diagnosed acute myeloid leukemia and myelodysplastic syndrome.

Preclinical data suggest that retinoids, eg, all-trans retinoic acid (ATRA), lower concentrations of antiapoptotic proteins such as bcl-2, possibly thereby improving the outcome of anti-acute myeloid leukemia (AML) chemotherapy. Granulocyte colony-stimulating factor (G-CSF) has been considered to be potentially synergistic with ATRA in this regard. Accordingly, we randomized 215 patients with newly diagnosed AML (153 patients) or high-risk myelodysplastic syndrome (MDS) (refractory anemia with excess blasts [RAEB] or RAEB-t, 62 patients) to receive fludarabine + ara-C + idarubicin (FAI) alone, FAI + ATRA, FAI + G-CSF, or FAI + ATRA + G-CSF. Eligibility required one of the following: age over 71 years, a history of abnormal blood counts before M.D. Anderson (MDA) presentation, secondary AML/MDS, failure to respond to one prior course of chemotherapy given outside MDA, or abnormal renal or hepatic function. For the two treatment arms containing ATRA, ATRA was given 2 days (day-2) before beginning and continued for 3 days after completion of FAI. For the two treatment arms including G-CSF, G-CSF began on day-1 and continued until neutrophil recovery. Patients with white blood cell (WBC) counts >50,000/microL began ATRA on day 1 and G-CSF on day 2. Events (death, failure to achieve complete remission [CR], or relapse from CR) have occurred in 77% of the 215 patients. Reflecting the poor prognosis of the patients entered, the CR rate was only 51%, median event-free survival (EFS) time once in CR was 36 weeks, and median survival time was 28 weeks. A Cox regression analysis indicated that, after accounting for patient prognostic variables, none of the three adjuvant treatment combinations (FAI + ATRA, FAI + G, FAI + ATRA + G) affected survival, EFS, or EFS once in CR compared with FAI. Similarly, there were no significant effects of either ATRA ignoring G-CSF, or of G-CSF ignoring ATRA. As previously found, a diagnosis of RAEB or RAEB-t rather than AML was insignificant. There were no indications that the effect of ATRA differed according to cytogenetic group, diagnosis (AML or MDS), or treatment schedule. Logistic regression analysis indicated that, after accounting for prognosis, addition of G-CSF +/- ATRA to FAI improved CR rate versus either FAI or FAI + ATRA, but G-CSF had no effect on the other outcomes. We conclude that addition of ATRA +/- G-CSF to FAI had no effect on CR rate, survival, EFS, or EFS in CR in poor prognosis, newly diagnosed AML or high-risk MDS.

Acute Disease↗
PubMed1999

A pilot study of interleukin-2 for adult patients with acute myelogenous leukemia in first complete remission.

BACKGROUND: Interleukin-2 (IL-2) has immunomodulatory effects, including stimulating the activity of cytotoxic T cells and natural killer cells, and inducing the generation of lymphokine-activated killer cells. The authors investigated whether IL-2 may improve the duration of complete remission (CR) and survival in acute myelogenous leukemia (AML) patients in first CR. METHODS: Eighteen patients were included after achieving a CR and receiving at least two courses of consolidation chemotherapy. Therapy was comprised of IL-2 4.5 x 10(5) U/m2 daily by continuous infusion (CI) for 12 weeks, plus boluses of 1 x 10(6) U/m2 on Day 8 and weekly thereafter while continuing the CI. No further chemotherapy was given after the administration of IL-2 was started. RESULTS: The median age of the patients was 50 years (range, 18-73 years), and 7 patients (39%) had an antecedent hematologic disorder (AHD). The median CR duration was 12 months, with 6 patients still alive in CR at a median follow-up of 64 months (range, 50-82 months). Long term CR by cytogenetics occurred in 2 of 5 patients with a normal karyotype (CR duration of 68+ months and 72+ months, respectively), 1 of 3 patients with t(8;21) (CR duration of 82+ months), 1 patient with inv(16) (CR duration of 67+ months), none of 2 patients with -5/-7 (1 patient died in CR after 10 months), 1 of 2 patients with abnormalities in chromosome 11 (CR duration of 60+ months), and 1 of 4 patients with miscellaneous abnormalities (CR duration of 74+ months). The median survival was 47 months. To assess the significance of these results, the authors selected two historic controls receiving long term postremission chemotherapy per each IL-2 case. The controls had remained in CR for at least as long as the cases when the latter underwent treatment initiation with IL-2 and were matched for the number of induction courses required to achieve CR, AHD, cytogenetic abnormalities, and age. Six of 18 IL-2 patients (33%) were alive in CR at 3 years compared with 7 of 36 controls (19%) (P = 0.31). Nine IL-2 patients (50%) were alive at 3 years compared with 10 controls (28%) (P = 0.13). CONCLUSIONS: These results suggest that IL-2 is tolerable in AML patients in first CR and should be studied further in future studies as a therapeutic strategy to prolong remission duration.

Adolescent↗
PubMed1999

Expression and function of leptin receptor isoforms in myeloid leukemia and myelodysplastic syndromes: proliferative and anti-apoptotic activities.

The receptor for the gene product of the obesity gene, leptin, was recently reported to be expressed on murine and human hematopoietic progenitor cells. Therefore, we studied the expression of the leptin receptor, OB-R, in normal myeloid precursors, human leukemia cell lines, and primary leukemic cells using reverse-transcriptase polymerase chain reaction. In normal hematopoiesis, OB-R was expressed in CD34(+) cells. Normal promyelocytes (CD34(-)33(+) and CD34(-)13(+)) expressed only very low levels of the short, presumably nonsignaling isoform. Both the long and short isoforms of OB-R were expressed in 10 of 22 samples from patients with newly diagnosed primary or secondary acute myeloid leukemia (AML), with a higher incidence of the long isoform in primary AML (87.6% v 28.6%; P =.01). The incidence of OB-R expression was higher in recurrent than in newly diagnosed AML (P <.001), and samples from four patients with refractory AML showed strong expression of both isoforms. Both OB-R isoforms were also expressed in newly diagnosed and recurrent acute promyelocytic leukemia cells but were essentially absent in samples of chronic or acute lymphocytic leukemia. In vitro growth of myeloid leukemic cell lines and of blasts from 14 primary AMLs demonstrated that recombinant human leptin alone induced low level proliferation, significantly (P <.05) increased proliferation induced by recombinant human granulocyte colony-stimulating factor, interleukin 3, and stem cell factor in a subset of AML and increased colony formation (P <.005). Also, leptin reduced apoptosis induced by cytokine withdrawal in MO7E and TF-1 cells. Serum leptin levels correlated only with body mass index (P <. 001) and gender (P =.03). Results confirm the reported expression of leptin receptor in normal CD34(+) cells and demonstrate the frequent expression of leptin receptors in AML blasts. While normal promyelocytes lack receptor expression, leukemic promyelocytes express both isoforms. We also demonstrate proliferative effects of leptin alone and in combination with other physiologic cytokines, and anti-apoptotic properties of leptin. These findings could have implications for the pathophysiology of AML.

Apoptosis↗
PubMed1999

A new statistical method for dose-finding based on efficacy and toxicity in early phase clinical trials.

Most statistical methods for dose-finding in phase I clinical trials determine a maximum tolerable dose based on toxicity while ignoring efficacy. Most phase II designs assume that an acceptable dose has been determined and aim to estimate treatment efficacy, possibly with early stopping rules for safety monitoring. The purpose of this paper is to describe a new statistical strategy for dose-finding in single-arm clinical trials where patient outcome is characterized in terms of both response and toxicity. The strategy, which may be considered a phase I/II hybrid, was first proposed by Thall and Russell [1] and subsequently modified by Thall [2]. The underlying mathematical model expresses the probabilities of response and toxicity as interdependent functions of dose. The method is based on fixed standards for the minimum probability of response and the maximum probability of toxicity appropriate for the particular trial. The best acceptable dose is chosen for each successive patient cohort adaptively, based on the fixed standards and the dose-outcome data from patients treated previously in the trial. The scientific goals are to select one best acceptable dose for future patients and to estimate the response and toxicity probabilities at that dose, or to stop the trial early if it becomes sufficiently unlikely that any dose is both safe and efficacious. An application of the method to a trial of donor lymphocyte infusion as salvage therapy for chemo-refractory AML/MDS patients is described. To illustrate the method's flexibility and potential breadth of application, two additional examples are provided, including a hypothetical trial in which a 5% response rate is of interest.

Clinical Trials as Topic↗
PubMed1999

Treatment of newly diagnosed AML, RAEB-t or RAEB with lisofylline or placebo in addition to chemotherapy.

To determine whether the addition of lisofylline (LSF) to idarubicin (12 mg/m2 daily x 3) + ara-C (1.5 g/m2 daily x 4) affects the rates of infection, serious infection, CR or mortality during remission induction of newly diagnosed AML, RAEB-t or RAEB, we randomized 70 patients to 3 mg/kg lisofylline or placebo every 6 h i.v., to begin 6 h before the first dose of idarubicin and to continue until recovery of neutrophil and platelet counts or for 28 days, whichever came first. Eligibility required that patients be below age 71 years, have no history of abnormal counts, or chemotherapy for a prior malignancy, and have a creatinine <1.6 mg/dl and bilirubin <3.0 mg/dl. The study was double-blinded and infections were tabulated separately and independently at MD Anderson and by a three-member outside panel of experts. Logistic regression was used to assess the relative effects of treatment arm (LSF or placebo), age, performance status, treatment site (laminar air flow room or not), and cytogenetics on rates of infection and serious infection following the first course of chemotherapy, and on CR rate. There were 84% and 87% concordance between the expert panel and MD Anderson enumerations of infection and serious infections, respectively. Both analyses found no significant (P < 0.05) differences between the rates of infection, or serious infection, in the placebo and LSF groups. CR, 60-day, and overall mortality rates were similar in the two groups, as were time to neutrophil and blood count recovery and outcome once in CR. Logistic regression analyses supported the above conclusions. Severe nausea/vomiting and mucositis were more frequent in the LSF group. Our results suggest that larger studies of LSF in newly diagnosed AML, RAEB-t, or RAEB are not warranted.

Acute Disease↗
PubMed1999

Secondary acute myeloid leukemia with inv(16): report of two cases following paclitaxel-containing chemotherapy and review of the role of intensified ara-C therapy.

Acute myeloid leukemia developing secondary to prior cytotoxic chemotherapy (s-AML) encompasses a range of distinct entities. We report two cases of s-AML with inv(16)(p13q22) who had prior exposure to paclitaxel. Additionally, two previously reported cases of s-AML with inv(16) had prior paclitaxel exposure raising the possibility that the taxanes may predispose to this specific syndrome of s-AML. One of our patients received escalated-dose ara-C chemotherapy, achieving a complete remission (12+ months). We therefore examined the prognosis of previously reported cases of s-AML with inv(16) and analyzed the influence of escalated-dose ara-C (>/=400 mg/m2/day). A total of 25 evaluable cases were identified, with 96% attaining CR independent of ara-C dose. The estimated median remission duration was 40 months and the median survival has not been reached (actuarial 5-year survival 52 +/- 18%). Although not achieving statistical significance, patients treated with escalated dose ara-C (n = 15) had longer remission duration and overall survival than those treated with standard dose ara-C (n = 10) (P = 0.063 and 0.20, respectively). In univariate analysis, younger age, male gender, and the presence of additional cytogenetic abnormalities were associated with a tendency towards adverse outcomes (P< 0.1). Age and gender were equally distributed between ara-C dose cohorts, but more patients treated with standard-dose ara-C had additional cytogenetic abnormalities (P = 0.048). Within the limitations of this retrospective study, this analysis suggests that, similar to de novo AML with inv(16), secondary cases may also potentially benefit from treatment with escalated-dose ara-C. This is consistent with the premise that the underlying molecular defect, rather than the presence of prior cytotoxic drug exposure, may be the most important determinant of disease behavior and chemotherapy responsiveness in AML.

Adenocarcinoma↗
PubMed1999

Expression of Bcl-2-related genes in normal and AML progenitors: changes induced by chemotherapy and retinoic acid.

The expression of Bcl-2 family members was examined in normal and leukemic hematopoietic cells. Immature hematopoietic progenitor cells (CD34+/33-/13-) did not express Bcl-2 but Bcl-XL, the majority of CD34 cells expressed Bcl-2, Bcl-XL and BAD, and normal promyelocytes (CD34-/33+) lacked expression of both Bcl-2 and Bcl-XL, while leukemic CD34+progenitors and promyelocytes expressed these anti-apoptotic proteins. In AML, Bcl-2 expression was higher on CD34+ than on all AML cells, however, expression of Bcl-2 or Bcl-XL did not predict achievement of complete remission. Surprisingly, low Bcl-2 content was associated with poor survival in a group of patients with poor prognosis cytogenetics. The anti-apoptotic BAD protein was found to be expressed in AML, but was phosphorylated in 41/42 samples. Phosphorylation was found at both sites, Ser 112 and Ser 136. During induction chemotherapy, Bcl-2 levels of CD34 cells increased significantly. In the context of evidence for small numbers of leukemic CD34+ cells expressing very high levels of Bcl-2 prior to therapy, this finding is interpreted as a survival advantage of Bcl-2 overexpressing progenitors and rapid elimination of cells with low Bcl-2. Bcl-2 and Bcl-XL were both expressed in minimal residual disease cells. Downregulation of Bcl-2 mRNA and protein was observed by ATRA and the combination of Ara-C, followed by ATRA, resulted in markedly increased cytotoxicity in HL-60 cells, as compared to Ara-C alone or ATRA followed by Ara-C. Implications of these findings for the development of new therapeutic strategies for AML are discussed.

Acute Disease↗
PubMed1999

Use of peripheral blood blasts vs bone marrow blasts for diagnosis of acute leukemia.

Acute leukemia can be diagnosed when blasts constitute 30% or more of the nucleated cells in a patient's peripheral blood (PB) sample. To determine whether in such cases bone marrow (BM) aspirates are still necessary, we compared the results of diagnostic studies performed on PB samples with blast counts of 30% or more with those performed on the same patients' BM samples. We found no differences in morphologic features, cytochemistry, or immunophenotype between the blasts in PB and BM samples in any of 30 cases studied. However, in 10 (23%) of 44 cases in which cytogenetic analysis was performed, PB but not BM samples were insufficient for analysis. The converse never occurred. Five of the 10 cases had acute lymphoblastic leukemia and 5 had acute myeloid leukemia (41% of the patients with acute lymphoblastic leukemia and 17% of the patients with acute myeloid leukemia). In cases with adequate metaphases, there was strong correlation between the cytogenetic results for PB and BM samples. Some PB samples with blast counts of 30% or more are adequate for diagnosis of acute leukemia, especially when therapy can be delayed until it is known that an adequate number of analyzable metaphases are recovered from the PB samples.

Acute Disease↗
PubMed1999

Comparison of touch imprints with aspirate smears for evaluating bone marrow specimens.

We compared the differential counts of normal and abnormal bone marrow from touch imprints with those from aspirate smears to determine whether the touch imprint was reliable for independent routine use in the examination of bone marrow and the classification of hematologic abnormalities. Normocellular bone marrow specimens were obtained from 87 patients without hematologic abnormality. Abnormal bone marrow specimens were obtained from 173 patients with treated or untreated neoplastic hematologic disease, including acute myeloid leukemia, myelodysplastic syndrome, chronic lymphocytic leukemia, non-Hodgkin lymphoma, hairy cell leukemia, myeloma, and acute lymphoblastic leukemia. We found no diagnostic difference in the differential counts from touch imprints and aspirate smears of normocellular bone marrow, and although we found some difference between the differential counts in certain cases of diseased bone marrow, the touch imprint proved to be a reliable diagnostic tool for determining the cellular composition of normal bone marrow and more reliable for the diagnosis of bone marrow involved by a neoplastic hematologic disease. Our findings suggest that evaluating touch imprints should be considered a standard practice in examining bone marrow.

Bone Marrow Cells↗
PubMed1998

Caspase 2 and caspase 3 protein levels as predictors of survival in acute myelogenous leukemia.

Because caspase activation is an essential step in programmed cell death (apoptosis) and cytotoxic drug-induced apoptosis is mediated by caspase 2 and caspase 3, we hypothesized that caspase 2 and 3 levels predict clinical outcome in acute myelogenous leukemia (AML). Using quantitative Western blot analysis, we studied the levels of nonactivated (uncleaved) caspase 2 and 3 in peripheral blood low-density cells from 185 patients with newly diagnosed AML. We also measured the level of activated (cleaved) caspase 3 in 41 randomly selected samples from the 185 patients. Finally, we analyzed the effect of caspase 2 and 3 levels and other prognostic variables on patient survival using a multivariate Cox model. We found that median levels of nonactivated caspase 2 and 3 were higher in AML than in normal peripheral blood cells (P < .001 and P <.02, respectively). There was no association between caspase level and either the percentage of peripheral blasts or any specific type of leukemia cell cytogenetic abnormalities. When the effect of each uncleaved caspase was considered individually, a high level of uncleaved caspase 3 (P = .04), but not of caspase 2 (P = .16), was associated with decreased survival. Conversely, a high level of cleaved caspase 3 denoted improved survival and correlated with the inactivation of the DNA-repair enzyme poly(ADP-ribose) polymerase. Thus, cleaved caspase 3 could stimulate the apoptotic cascade further, and lack of its activation likely caused an accumulation of the uncleaved caspase. Although uncleaved caspase 2 level per se had no prognostic significance, the interactive effect of high levels of both uncleaved caspase 2 and 3 denoted very poor survival (P < .001) and had the largest effect of all prognostic variables (P < .001; estimated relative risk, 2.49; 95% confidence interval, 1.59 to 3. 90). Taken together, caspase 2 and caspase 3 protein levels obtained at diagnosis may constitute a reliable prognostic factor in AML.

Acute Disease↗
PubMed1998

Thrombopoietin stimulates myelodysplastic syndrome granulocyte-macrophage and erythroid progenitor proliferation.

Thrombopoietin (TPO) has been successfully used to stimulate megakaryocyte progenitor proliferation and platelet production both in vitro and in vivo. We and other investigators have found that TPO also stimulates normal marrow colony-forming unit granulocyte-macrophage (CFU-GM) and burst-forming unit-erythroid (BFU-E) growth. In contrast to its effect on normal marrow precursors, TPO stimulates acute myelogenous leukemia (AML) progenitor proliferation in only 25% of the cases. Because the hematopoietic cells in Myelodysplastic syndrome (MDS) originate from both the normal and leukemic clones, we hypothesized that TPO may be a useful therapeutic agent for MDS. To test this hypothesis, we used fresh marrow samples taken from 14 MDS patients. We found that in the presence of fetal calf serum (FCS) and erythropoietin (EPO) TPO (5 to 40 ng/ml) MDS CFU-GM and BFU-E colony-forming cell proliferation were stimulated in a dose-dependent fashion by up to 103% and 93% respectively. This effect was similar to the stimulation obtained with optimal concentrations of granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage CSF (GM-CSF), or interleukin-3 (IL-3). Furthermore, TPO increased the colony-stimulatory effects of G-CSF, GM-CSF, IL-3, and stem cell factor (SCF) on MDS marrow cells. However, depletion of either T lymphocytes or adherent cells abrogated the effect of TPO, suggesting that the effect is not a direct one but is mediated through interaction with cytokines produced by accessory cells. Taken together, our data suggest that the therapeutic role of TPO in the management of MDS warrants further investigation.

Aged↗
PubMed1998

Incorporating new modalities into guidelines. Topotecan for myelodysplastic syndromes.

The National Comprehensive Cancer Network (NCCN) guidelines for patients with myelodysplastic syndromes (MDS) list myelosuppressive chemotherapy as an option for patients who have MDS with International Prognostic Scoring System (IPSS) scores of "intermediate" or "high." Myelodysplastic syndromes with these IPSS scores have an unfavorable natural history. Topotecan is a myelosuppressive drug that interacts with topoisomerase I and that has been used in the treatment of refractory AML. Its use in MDS has recently received considerable publicity. This paper reviews M. D. Anderson's results with topotecan and topotecan + ara-C in patients with MDS, focusing on comparisons of the results with ara-C and ara-C + fludarabine +/- idarubicin. While it is clear that the drug can produce complete responses, it is less clear that it differs from these other regimens. On average, complete response and survival rates are similar following administration of topotecan + ara-C or the other regimens. On the other hand, among patients with abnormalities of chromosomes 5 and/or 7, complete response rates are higher following topotecan + ara-C than for ara-C alone, or other ara-C combinations. The improvement in complete response rate among patients with abnormalities of chromosomes 5 and/or 7 has not resulted in an improvement in their survival (actuarial median about 6 months), largely reflecting a poor outcome following complete response. Indeed, the frequency of relapse in these patients suggests that any inherent increase in antileukemia activity in patients with abnormalities of chromosomes 5 and/or 7 is minimal. Given the overall results, topotecan +/- ara-C should not be regarded as standard therapy for MDS. The drug is nonetheless interesting and attempts to add to its efficacy are in progress.

Aged↗
PubMed1998

Prognosis and therapy of secondary myelodysplastic syndromes.

This is an invited review of a condition that is likely to become increasingly frequent in coming years. The objective is to define the varying prognoses of the condition and to discuss treatment options for patients with better and worse prognoses. The source of the data is the literature. Of particular note are the paper by Greenberg et al. describing the International Prognostic Scoring System for MDS and that by Estey et al. describing the similar response of AML, RAEB-t, and RAEB to AML-type chemotherapy. The state of the art is that no satisfactory therapeutic options exist; consequently, the majority of patients with secondary MDS should participate in clinical trials.

Antineoplastic Combined Chemotherapy Protocols↗