Search PubMed⌕ Search

Biomedical subjects

E Estey

Publications and source records attributed to E Estey.

At least 55 records · Page 3Linked to original sources
PubMed2000

Cyclophosphamide, ara-C and topotecan (CAT) for patients with refractory or relapsed acute leukemia.

Topotecan is a topoisomerase I inhibitor with significant activity in patients with myelodysplastic syndrome and chronic myelomonocytic leukemia. Pre-clinical data suggest a synergistic activity with DNA damaging agents such as cyclophosphamide, where topotecan might prevent the repair of cyclophosphamide-induced DNA damage. We thus designed a combination including cyclophosphamide 500 mg/m2 every 12 hours given on days 1 to 3; topotecan 1.25 mg/m2/day by continuous infusion on days 2 to 6, and cytosine arabinoside (ara-C) 2 g/m2 over 4 hours daily for 5 days on days 2 to 6 (CAT). Sixty six (63 evaluable) patients were treated. Fifty two patients had refractory (n=12) or relapsed (n=40) acute myelogenous leukemia (AML), and eleven had acute lymphocytic leukemia (ALL) (refractory n=3, relapsed n=8); their median age was 57 years (range, 18 to 79 years). Eleven patients (17%) achieved a complete remission (CR), and two patients (3%) had a hematologic improvement (HI; met all criteria for CR except for platelets < 100x10(9)/L), for an overall response rate of 20%. Responses occurred in 12 of 52 AML patients (23%), including 10 CR (19%) and 2 HI (4%), and in 1 of 11 patients with ALL (9%). Myelosuppression was universal; there were 23 episodes of pneumonia or sepsis and 18 episodes of fever of unknown origin complicating 74 courses of CAT. Non-hematologic toxicity was mostly gastrointestinal, including nausea, vomiting, diarrhea and mucositis, but was severe in only 8%. In summary, the CAT regimen is well tolerated and has significant anti-leukemia activity which warrants further investigation.

Acute Disease↗
PubMed1999

A phase I-II trial of escalating doses of mitoxantrone with fixed doses of cytarabine plus fludarabine as salvage therapy for patients with acute leukemia and the blastic phase of chronic myelogenous leukemia.

BACKGROUND: Cytarabine is an essential drug for inducing remission of acute myelogenous leukemia, and it is also one the most effective drugs used as salvage therapy for patients with all types of relapsed acute leukemia. Nevertheless, there is considerable room for improvement in the treatment of patients with relapsed leukemia in terms of both the reinduction rate and the duration of response. Fludarabine has been shown to augment responses to cytarabine, possibly by increasing the intracellular concentrations of the active metabolite cytarabine triphosphate. Higher-than-standard doses of mitoxantrone have been shown to augment responses to cytarabine, possibly by increasing the DNA strand breaks induced by topoisomerase II; these strand breaks cannot be effectively repaired in the presence of cytarabine triphosphate. This preliminary study was designed to determine whether moderately high doses of mitoxantrone could be added to the combination of fludarabine and cytarabine in an attempt to improve the combination's antileukemic efficacy. METHODS: Fifty-five adults with relapsed or refractory acute leukemia or the blastic phase of chronic myelogenous leukemia (CML) received salvage therapy with the FLAM regimen, which consisted of fludarabine, cytarabine, and increasing doses of mitoxantrone. RESULTS: Even with doses of mitoxantrone escalated to as much as 60 mg/m(2) over 4 days, dose-limiting toxicity was not observed. Overall, the complete response rate was 27.3% (15 of 55 patients, including 4 of 17 with acute myelogenous leukemia [AML], 4 of 12 with acute lymphocytic leukemia [ALL], and 7 of 26 with the blastic phase of CML). The median time to complete response was 42 days. Toxicity other than myelosuppression was manifested primarily as hyperbilirubinemia, which was reversible in all cases. Poor performance status and undifferentiated blastic phase of CML were poor prognostic factors for response to FLAM. CONCLUSIONS: The FLAM regimen is an active salvage regimen and should be formally evaluated in Phase II studies of patients with AML, ALL, and the myeloid and lymphoid blastic phases of CML.

Adolescent↗
PubMed1999

Cellular vascular endothelial growth factor is a predictor of outcome in patients with acute myeloid leukemia.

Vascular endothelial growth factor (VEGF) is a potent mitogen for vascular endothelial cells. It has been associated with angiogenesis, growth, dissemination, metastasis, and poor outcome in solid tumors. To assess cellular VEGF levels and their prognostic significance in newly diagnosed acute myeloid leukemia (AML), we used a radioimmunoassay (RIA) to quantify VEGF levels in stored samples obtained before treatment from 99 patients with newly diagnosed AML treated at the MD Anderson Cancer Center from 1996 to 1998. Outcome in the 99 patients was representative of that observed in all patients seen at this institution with this diagnosis during these years, but the 99 patients had higher white blood cell (WBC) and blast counts than the other patients. Results of the RIA were confirmed by Western blot. There was a relationship between increasing VEGF levels and shorter survival (P =.01), as well as shorter disease-free survival, both from start of treatment and from complete response (CR) date. In contrast, there was no relationship between VEGF level and WBC or blast count, or between VEGF level and such established prognostic factors as age, cytogenetics, performance status, or presence of an antecedent hematologic disorder, and multivariate analysis indicated that VEGF was still prognostic for the above outcomes after accounting for these factors, as well as treatment. Our results suggest that at least in AML patients with higher WBC and blast counts, cellular VEGF level is an independent predictor of outcome.

Acute Disease↗
PubMed1999

Correlation between lower c-mpl protein expression and favorable cytogenetic groups in acute myeloid leukemia.

The gene for the thrombopoietin receptor, c-mpl, has been shown to be overexpressed at the mRNA level in acute myeloid leukemia (AML) and myelodysplastic syndrome. A recent study reported c-mpl mRNA overexpression in 60% of a small sample of AML patients, and this overexpression correlates with shorter complete remission but not with karyotype group. We quantified c-mpl protein expression in 107 cases of AML and 24 normal bone marrow and 12 normal peripheral blood samples by using Western blot analysis and radioimmunoassay (RIA). Western blot analysis revealed no detectable level of c-mpl protein in the normal samples, whereas trace amounts were detected by RIA. c-mpl protein expression was increased (> or = twice normal) in 65% of the AML cases. c-mpl protein expression was correlated with cytogenetic groups (P = 0.0009, Kruskal-Wallis test in rejecting the hypothesis that c-mpl expression was the same in different groups). Specifically, patients with favorable cytogenetic groups (t(8;21), inv16, and t(15;17)) had lower c-mpl protein expression (median 1.7 times normal), whereas patients with unfavorable abnormalities (+8, -5 or -7, and del(11)(q23)) and normal cytogenetics had high expression (3.1 and 2.85 times normal, respectively). The findings were the same when only the 61 untreated AML patients were considered. No statistically significant correlation between c-mpl expression and age or antecedent hematologic disorder was found. These results suggest that c-mpl protein overexpression in AML may play a role in the aggressiveness of this disease.

Blotting, Western↗
PubMed1999

Phase I study of liposomal daunorubicin in patients with acute leukemia.

The dose of anthracyclines used during induction has been identified as a significant prognostic factor in acute leukemias. Liposomal encapsulation of anthracyclines has been proposed as a way of decreasing toxicity and probably increasing efficacy of these agents, therefore allowing the exploration of high-dose anthracycline therapy in acute leukemias. We conducted a phase I study of liposomal daunorubicin (Daunoxome; DNX) in patients with refractory or relapsed acute leukemias. Patients received three daily doses of DNX at 75, 100, 150 or 200 mg/m2 on each cycle, to a total dose of 225, 300, 450, and 600 mg/m2, respectively. At least three patients were included at each dose level before escalating to the next level, and patients could receive more than one course at the next dose level. Twenty-four patients were included and 23 are evaluable. Fifteen patients received one course, seven received two courses, and one received three courses of DNX. Seventeen patients had previously received anthracyclines. The dose-limiting toxicity was mucositis which occurred (grade 3-4) in 3 of 5 patients treated at 200 mg/m2, 2 of 9 treated at 150 mg/m2 and 1 of 6 at 100 mg/m2. Other non-hematologic toxicity was mild and infrequent. There was no change in post-LVEF among 9 patients with available data and no significant cardiac events were documented. Two patients had a complete response: one patient with chronic myeloid leukemia in refractory blast phase went back to chronic phase, and one patient with second relapse acute promyelocytic leukemia achieved a third complete remission. We conclude that the maximally tolerated dose of DNX in this schedule is 150 mg/m2 and has significant anti-leukemia activity.

Acute Disease↗
PubMed1999

Combination of topotecan with cytarabine or etoposide in patients with refractory or relapsed acute myeloid leukemia: results of a randomized phase I/II study.

The topoisomerase I inhibitor topotecan has shown activity in acute myeloid leukemia (AML) and myelodysplastic syndromes. The present study was designed to assess whether topotecan with cytosine arabinoside (ara-C) or with etoposide (VP-16) should be studied in phase II trials in patients with refractory or relapsed AML. Patients with refractory or relapsed AML were assigned to one of 3 strata defined by expected CR rates of 7%, 20% and 40%, then randomly assigned to receive topotecan (dl-5) and ara-C (1 g/m2 over 2 hours; dl-5), topotecan (d1-5) followed by VP-16 (250 mg/m2 twice daily, d6-7), or VP-16 (250 mg/m2 twice daily dl-2) followed by topotecan (d3-d7). A dose-finding phase was conducted in the poorest stratum of each arm (topotecan starting dose: 1.0 mg/m2/day x 5). A Bayesian pre-phase II selection design was used to assess whether the CR rate with a given arm was sufficient to merit investigation in phase II. Thirty-seven patients, median age 58 years, were treated. Their median first CR duration was 28 weeks and 24% were primary refractory. Grade 3-4 mucositis occurred in the initial patients in the topotecan --> VP-16, but not in the topotecan + ara-C or VP-16 --> topotecan arms. Consequently, in subsequent patients, the topotecan dose was lower in the topotecan --> VP-16 than in the other 2 arms (1.0 vs 1.25 mg/m2 daily x 5) and the VP-16 dose was lower in the topotecan --> VP-16 arm (200 vs 250 mg/m2 twice daily x 2). One CR occurred (topotecan --> VP-16 arm), and the treatment arms were terminated after 10, 15, and 12 patients were treated on the topotecan + ara-C, topotecan --> VP-16, and VP-16 --> topotecan arms, respectively. The principal cause of failure was insufficient anti-leukemia effect rather than death on study, and toxicity was minimal at the final doses used. We concluded that none of the combinations studied here warrants phase II evaluation in very poor prognosis AML salvage patients.

Adolescent↗
PubMed1999

Phase I and pharmacologic study of 9-aminocamptothecin colloidal dispersion formulation in patients with refractory or relapsed acute leukemia.

PURPOSE: Topoisomerase I inhibitors have shown promising anti leukemic activity in acute myelogenous leukemia (AML) and myelodysplastic syndrome. In this phase I study, we investigated the toxicity profile, pharmacokinetics, and activity of a prolonged continuous infusion schedule of the colloidal dispersion formulation of 9-amino-camptothecin (9-AC/CD) in patients with acute leukemia. PATIENTS AND METHODS: Patients with refractory or relapsed AML, acute lymphocytic leukemia (ALL) or chronic myelogenous leukemia in blastic phase (CML-BP) were included in the study. Eligibility criteria were age greater than 15 years, performance status of 2 or better, creatinine < 1.5 mg/dl, and bilirubin < 1.5 mg/dl. 9-AC/CD was given as a continuous intravenous infusion over seven days every three to four weeks. The starting dose was 0.2 mg/m2/d (1.4 mg/m2/course). Courses were given every three to four weeks according to toxicity and anti leukemic efficacy. This phase I study used the classical 3 + 3 design. The dose was escalated by 50% until grade I toxicity was observed, and then by 30% to 35% until the dose limiting toxicity was defined. At the maximal tolerated dose (MTD), 8 to 10 patients were planned to be treated to better define the toxicity and early-activity profiles. RESULTS: Thirty-nine patients (AML thirty-six patients; ALL two patients; CML-BP one patient), median age 56 years, were treated. Severe mucositis was the dose limiting toxicity; it occurred in three of six patients treated at a dose of 1.6 mg/m2/d. The MTD was defined as 1.4 mg/m2/day by the phase I design. Upon expansion of the number of patients, 3 of 10 patients had grade 4 mucositis and 1 of 10 patients had grade 3 diarrhea. Nausea and vomiting were uncommon. No complete or partial remission was observed in 37 evaluable patients. However, 9-AC/CD exhibited antileukemic activity, as reflected by the finding of marrow hypoplasia on day 14 in 46% of the patients. Average steady-state concentration of 9-AC lactone was close to 10 nmol/l, and the of 9-AC lactone area under curve (AUC) was 1409 +/- 705 nmol/l. hr. CONCLUSION: The MTD of 9-AC/CD given as a seven-day continuous infusion was 1.4 mg/m2/d (9.8 mg/m2/course) in patients with acute leukemia. This represents three to fourfold dose escalation compared with the MTD of 9-AC given as shorter continuous infusion (three days) in patients with solid tumors. Future studies will determine the activity of prolonged administration of 9-AC/CD in patients with better prognosis acute leukemia.

Adult↗
PubMed1999

Granulocytic sarcoma of the pancreas: a report of two cases and literature review.

Granulocytic sarcomas (GS) are extramedullary tumour masses of immature myeloid cells, also known as chloroma and extramedullary myeloid cell tumour. These neoplasms usually occur simultaneously with, or follow the onset of acute myeloid leukaemia (AML). Rarely, they are the first manifestation of AML. GS may also be the first sign of transformation to AML in patients with chronic myeloproliferative disorders and myelodysplastic syndromes. GS have been reported to occur in a variety of tissues, but presentation as an abdominal mass and, in particular, infiltration of the pancreas is rare. We report two cases of pancreatic GS, review the literature, and discuss recent insights into the basic biological properties of these rare tumours.

Adult↗
PubMed1999

CD56 expression in acute promyelocytic leukemia: a possible indicator of poor treatment outcome?

PURPOSE: Blast expression of CD56 is frequent in patients with t(8;21)(q22;q22) acute myeloid leukemia and is associated with an inferior outcome. The expression of CD56 has rarely been reported in acute promyelocytic leukemia (APL) and has not been clinically characterized. Therefore, we examined the prognostic significance of CD56 expression in APL. PATIENTS AND METHODS: We identified all reported cases of CD56+ APL in the medical literature and collected clinical, biologic, and therapeutic details. RESULTS: Data were obtained for 12 patients with CD56+ APL (> 20% blast expression of CD56), including four cases from a single institution with a total of 42 APL patients. All of the CD56+ APL patients had documented cytogenetic presence of t(15;17), and of the nine reported isotypes, eight (89%) were S-isoform. Only six CD56+ patients (50%) attained complete remission (CR); the other six individuals died within 35 days of presentation. Of the six patients who attained a CR, three (50%) relapsed at 111, 121, and 155 weeks, whereas three remained in continuous CR at 19, 90, and 109 weeks. Comparison of the control CD56- to CD56+ APL patients demonstrated that the latter group had a significantly lower fibrinogen level (P = .007), and among patients for whom data were available, there was a higher frequency of the S-isoform (P = .006). Additionally, the CR rate (50% v 84%, P = .025) and overall median survival (5 v 232 weeks; P = .019) were significantly inferior for CD56+ APL patients. CONCLUSION: CD56+ acute promyelocytic leukemia is infrequent, seems to occur more frequently with the S-isoform subtype, and may be associated with a lower CR rate and inferior overall survival.

Adult↗
PubMed1999

Topotecan and cytarabine is an active combination regimen in myelodysplastic syndromes and chronic myelomonocytic leukemia.

PURPOSE: To evaluate the efficacy and safety of the combination of topotecan and cytarabine in patients with myelodysplastic syndromes (MDSs) and chronic myelomonocytic leukemia (CMML). PATIENTS AND METHODS: Fifty-nine patients with MDSs and 27 with CMML were enrolled. They were either previously untreated (66%) or had received only biologic agents (14%) or chemotherapy with or without biologic agents (20%). Treatment consisted of topotecan 1.25 mg/m(2) by continuous intravenous infusion daily for 5 days and cytarabine 1. 0 g/m(2) by infusion over 2 hours daily for 5 days. Prophylaxis included antibacterial, antifungal, and antiviral agents. At a median follow-up of 7 months, all 86 patients were assessable for response and toxicity. RESULTS: Complete remission (CR) was observed in 48 patients (56%; 61% with MDSs, 44% with CMML; P =.15). Similar CR rates were observed for patients with good-risk and poor-risk MDS (70% and 56%, respectively). The treatment effectively induced CR in patients with a poor-prognosis karyotype involving chromosomes 5 and 7 (CR, 71%) and secondary MDSs (CR, 72%). Fifty-four patients received one induction course, 25 patients received two, and the rest received more than two. The median number of continuation courses was two. The median overall duration of CR was 34 weeks (50 weeks for MDSs and 33 weeks for CMML). The median survival was 60 weeks for MDS and 44 weeks for CMML patients. CR and survival durations were longer in patients with refractory anemia with excess blasts (RAEB). Grade 3 or 4 mucositis or diarrhea was observed in three patients each. Fever was observed in 63%, and infections in 49% of patients. Six patients (7%) died during induction therapy. CONCLUSION: Topotecan and cytarabine induced high CR rates in unselected patients with MDSs and CMML, particularly among patients with poor-prognosis cytogenetics and secondary MDSs. Topotecan-cytarabine is an active induction regimen in MDS and CMML patients, is well tolerated, and is associated with a low mortality rate.

Adult↗
PubMed1999

Phase I study of arabinosyl-5-azacytidine (fazarabine) in adult acute leukemia and chronic myelogenous leukemia in blastic phase.

Fazarabine has demonstrated a broad spectrum of antitumor activity in experimental models including P388 and L1210 cell lines. Previous phase I clinical trials using a 3-day continuous infusion schedule of Fazarabine have shown myelosuppression to be the dose limiting toxicity in solid tumors. Based on this clinical and preclinical experience we designed a phase I study to determine the toxicity, maximum tolerated dose (MTD), and antileukemic efficacy of Fazarabine using a 3-day continuous infusion schedule in patients with refractory or relapsed acute leukemia or chronic myelogenous (CML) in blastic phase. Adults with a diagnosis of acute leukemia or blastic phase CML who were refractory or had relapsed on salvage chemotherapy were entered on study. Fazarabine was administered as a continuous infusion over 3 days every 3 to 4 weeks. The initial dose was 2 mg/m2/hour x 72 hours. Results showed that the MTD was 425 mg/m2/hour infused over 72 hours every 3 to 4 weeks. At this dose level neurotoxicity and fluid overload were the dose limiting toxicities. Among 71 patients treated, we observed one complete remission, one partial remission and one hematologic improvement. No obvious dose response relationship could be determined. In conclusion, Fazarabine has not shown a beneficial effect in the therapy of acute leukemia. Since 71 patients and 20 dose levels were required to determine the MTD of Fazarabine, a reassessment of our phase I study designs should be considered to provide patients with better potential toxic: therapeutic benefits in such trials.

Adolescent↗
PubMed1999

The prognostic impact of BCL2 protein expression in acute myelogenous leukemia varies with cytogenetics.

BCL2 protein exerts an antiapoptotic effect on cells and decreases chemosensitivity. To determine whether BCL2 expression is prognostic of patient outcome in acute myelogenous leukemia (AML), we measured its level in 198 newly diagnosed, untreated AML patients by Western blotting using whole-cell lysates from low-density peripheral blood cells. BCL2 expression was not associated with the percentage of blasts (R2 = 0.10), French-American-British classification type, or cytogenetic abnormality. Smoothed martingale residual plots indicated that high BCL2 protein level was an adverse prognostic factor for patients with either favorable or intermediate prognosis cytogenetics [FIPC; inv(16), t(8:21), t(15:17), or diploid or insufficient metaphases] but was a favorable prognostic factor for patients with unfavorable prognosis cytogenetics (UC; -5, -7, +8, 11q23, Ph1, or miscellaneous changes). Patients with FIPC and high BCL2 (highest quartile) had a significantly shorter median survival (78 weeks versus not reached; P = 0.009) than did those with lower (lower three quartiles) levels of BCL2. Among those with UC, as BCL2 level decreased from the fourth quartile to the third or the combined first and second quartiles, the median survival decreased (from 94 to 45 or 17 weeks, respectively; P = 0.003). Lower expression of BCL2 in UC was associated with shorter remission duration (P = 0.05). In multivariate analyses performed using either overall or event-free survival as the end point, for either all patients or within either cytogenetic subgroup, BCL2 level was an independent prognostic factor. Similar analysis revealed that BCL2 level was an independent predictor of remission duration for UC patients as well. These data suggest that BCL2 is involved differently in different types (favorable versus unfavorable) of AML and that therapeutic strategies aimed at modulating BCL2 function may be more likely to work in patients with favorable cytogenetic abnormalities.

Adolescent↗
PubMed1998

Long-term follow-up of patients with chronic lymphocytic leukemia (CLL) receiving fludarabine regimens as initial therapy.

One hundred seventy-four patients with progressive or advanced chronic lymphocytic leukemia (CLL) have received initial therapy with fludarabine as a single agent or fludarabine combined with prednisone. The overall response rate was 78% and the median survival was 63 months. No difference in response rate or survival was noted in the 71 patients receiving fludarabine as a single agent compared with the 103 patients who received prednisone in addition. The median time to progression of responders was 31 months and the overall median survival was 74 months. Patients over the age of 70 years had shorter survivals. Patients with advanced stage disease (Rai III and IV) had a somewhat shorter survival than earlier stage patients. More than half the patients who relapsed after fludarabine therapy responded to salvage treatment, usually with fludarabine-based regimens. Second remissions were more common in patients who had achieved a complete remission on their initial treatment. The CD4 and CD8 T-lymphocyte subpopulations decreased to levels in the range of 150 to 200/microL after the first 3 courses of treatment. Although recovery towards normal levels was slow, the incidence of infections was low in patients in remission (1 episode of infection for every 3.33 patient years at risk) and decreased with time off treatment. There was no association of infections or febrile episodes with the use of corticosteroids or the CD4 count at the end of treatment and a poor correlation with the increase in CD4 counts during remission. Infectious episodes were less common in patients who had a complete response compared with partial responders. Richter's transformation occurred in 9 patients and Hodgkin's disease occurred in 4 patients. Five other patients died from other second malignancies. Fludarabine appears to be an effective initial induction therapy with a reasonable safety profile for patients with CLL.

Adult↗
PubMed1998

Comparison of referring and tertiary cancer center physician's diagnoses in patients with leukemia.

PURPOSE: To analyze the rates of concordance in the diagnosis of various hematological malignancies among patients referred to a tertiary cancer center, comparing the referring diagnosis with the final diagnosis at the M.D. Anderson Cancer Center. PATIENTS AND METHODS: This was a cross-sectional study analyzing the 409 patients referred to the M.D. Anderson Leukemia Service in 1995 in whom a bone marrow examination was performed by the referring physician and in whom this examination was repeated at our institution. We also analyzed 100 cases, including 84 of the 409 referred patients for whom the diagnostic outside bone marrow slide had been sent for review. RESULTS: The overall concordance rate was 73%. In 18% discordances were present and considered of major importance (affecting treatment and/or prognosis) while in 9% there were minor discordances. Major discordance rates were 2% for chronic lymphocytic leukemic leukemia and 5% for chronic myelogenous leukemia, but 29% for acute myelogenous leukemia (79 patients), 43% for acute promyelocytic leukemia (7 patients), 19% for acute lymphocytic leukemia (42 patients), 57% for hairy cell leukemia (7 patients), and 23% for the myelodysplastic syndromes (75 patients). The concordance rate was 76% in the 100 cases in which bone marrow specimens permitted comparison of the morphologic diagnosis made by M.D. Anderson and the referring physician using the same slide, with a rate of 75% in the acute leukemias as finally diagnosed at our institution. CONCLUSION: Although in the majority of cases the referring physicians and the specialty service agreed on diagnosis, major discordance occurs in a significant number of cases, including highly treatable diseases such as acute promyelocystic leukemia and hairy cell leukemia.

Bone Marrow↗