Biomedical subjects

Jorge Cortes

Publications and source records attributed to Jorge Cortes.

At least 55 records · Page 3Linked to original sources

PubMed2006

Clofarabine and cytarabine combination as induction therapy for acute myeloid leukemia (AML) in patients 50 years of age or older.

Outcome of patients with acute myeloid leukemia (AML) who are older than 60 years of age remains unsatisfactory, with low remission rates and poor overall survival. We have previously established the activity of clofarabine plus cytarabine in AML relapse. We have now conducted a phase 2 study of clofarabine plus cytarabine in patients aged 50 years or older with previously untreated AML. Clofarabine was given at 40 mg/m2 as a 1-hour intravenous infusion for 5 days (days 2 to 6) followed 4 hours later by cytarabine at 1 g/m2/d as a 2-hour intravenous infusion for 5 days (days 1 to 5). Of 60 patients, 29 (48%) had secondary AML, 30 (50%) had abnormal karyotypes (monosomy 5 and/or 7 in 15 [25%]), and 11 (21%) showed FLT3 abnormalities. The overall response (OR) rate was 60% (52% CR, 8% CRp). Four patients (7%) died during induction. Adverse events were mainly grade 2 or lower and included diarrhea, nausea, vomiting, mucositis, skin reactions, liver test abnormalities, and infusion-related facial flushing and headaches. Myelosuppression was common. Clofarabine plus cytarabine has activity in adult AML, achieving a good CR rate. However, survival does not appear to be improved compared with other regimens. Modifications of this combination in AML therapy of older patients warrant further evaluation.

Acute Disease↗

PubMed2006

Phase II study of sphingosomal vincristine in patients with recurrent or refractory adult acute lymphocytic leukemia.

BACKGROUND: Outcomes with salvage therapy for patients with recurrent or refractory acute lymphocytic leukemia (ALL) are poor, with complete response (CR) rates reported to be 20-30% and a median survival ranging from 2-6 months. New agents are needed to reduce the recurrence rate after frontline chemotherapy. Vincristine is an important component of ALL therapy. In animal models, the encapsulation of vincristine into sphingomyelin liposomes or "sphingosomes" for injection (SV) has improved efficacy compared with conventional vincristine. METHODS: A Phase II clinical trial of single-agent SV given at a dose of 2.0 mg/m2 every 2 weeks was conducted in patients with recurrent or refractory ALL. Approximately half of the 16 patients who received SV had a first CR duration of less than 1 year, 19% had failed standard induction chemotherapy, and 50% had Philadelphia chromosome-positive disease. SV was the first salvage attempt in 69% of the patients. RESULTS: The overall response rate in the 14 evaluable patients was 14% (1 CR and 1 partial response). Five patients (36%) had transient reductions in bone marrow leukemia infiltrate with subsequent regrowth of the leukemia between SV infusions. Toxicity with limited treatment (median number of doses was two; range, one to five doses) was minimal with expected peripheral neuropathy. CONCLUSIONS: Further study of SV in patients with ALL is warranted. A Phase I-II clinical trial of weekly SV with pulse dexamethasone currently is ongoing.

Adolescent↗

PubMed2006

Novel tyrosine kinase inhibitors in chronic myelogenous leukemia.

PURPOSE OF REVIEW: The successful introduction of the tyrosine kinase inhibitors has initiated a new era in the management of chronic myeloid leukemia. RECENT FINDINGS: Imatinib therapy has significantly improved prognosis of chronic myeloid leukemia. A minority of patients with chronic-phase disease (4% annually) and considerably more in advanced stages develop resistance. This is attributed, in 40-50% of cases, to the development of BCR-ABL (breakpoint cluster region/Abelson oncogene) tyrosine kinase domain mutations that impair imatinib binding. This has led to the development of more potent novel tyrosine kinase inhibitors that can overcome both BCR-ABL-dependent and BCR-ABL-independent mechanisms of resistance. Preliminary results of phase I and II trials with dasatinib and nilotinib have provided promising data that may reduce disease progression and potentially prevent acquired resistance to the tyrosine kinase inhibitors. SUMMARY: Novel tyrosine kinase inhibitors with more potent and selective Bcr-Abl inhibition and with multitargeted inhibition of Bcr-Abl and Src family kinases are promising and may further improve prognosis in chronic myeloid leukemia.

Clinical Trials as Topic↗

PubMed2006

Overcoming drug resistance in chronic myeloid leukemia.

PURPOSE OF REVIEW: Despite the excellent clinical results with imatinib in chronic myeloid leukemia, most patients have minimal residual disease and others will develop resistance and may eventually progress. Thus there is a need for developing approaches to overcome and prevent resistance to imatinib. RECENT FINDINGS: Several new agents have been developed with significant activity in imatinib-resistant chronic myeloid leukemia. A second generation of more potent tyrosine kinase inhibitors, some with dual activity against Abl and Src, have shown very impressive results. Other agents, such as hypomethylating agents, farnesyl transferase inhibitors and homoharringtonine, have also shown preclinical and clinical promise. The use of vaccines as a way of providing an immunomodulatory approach to chronic myeloid leukemia is starting to develop as a major strategy to achieve eradication of the disease. SUMMARY: Multiple effective agents are being developed to overcome resistance to imatinib. The challenge for the future is to incorporate them into effective strategies that can eliminate the disease and cure all patients with chronic myeloid leukemia.

Animals↗

PubMed2006

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

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

Adolescent↗

PubMed2006

New strategies in chronic myeloid leukemia.

Most patients with chronic myeloid leukemia (CML) achieve clinically relevant hematologic and cytogenetic responses to imatinib. Patients who show resistance to imatinib need new therapeutic options. A range of options are being developed to treat imatinib-resistant patients who have CML. Promising results of early-phase clinical trials have been reported for new tyrosine kinase inhibitors, farnesyl transferase inhibitors, decitabine, homoharringtonine, and vaccines. Further clinical trials are needed to characterize the efficacy and safety profile of these new agents and to determine which agents improve the long-term prognosis for patients with CML who have shown resistance to imatinib.

Angiogenesis Inhibitors↗

PubMed2006

[Anti-microbial resistance in intensive care units in Bogotá, Colombia, 2001-2003].

OBJECTIVES: Determining the frequency of antimicrobial resistance amongst bacterial isolates obtained from patients in Intensive Care Units (ICU). METHODS: Study data relating to 2001 to 2003 regarding microbiological isolates was obtained from a laboratory network for the ICUs of 14 third-level hospitals in Bogotá belonging to the Bogotá Bacterial Resistance Control Group (BBRCG). 27,301 isolates were obtained and their susceptibility profiles were analysed using WHONET 5.3. RESULTS: Staphylococcus aureus, Escherichia coli, coagulase negative Staphylococci (CNS), Pseudomonas aeruginosa y Klebsiella pneumoniae were the most commonly found microorganisms. Oxacillin-resistance rate ranged from 61% at 63% during 2001 to 2003 amongst S. aureus isolates and 78% to 83% amongst coagulase negative Staphylococci (CNS). E. coli resistance to third generation cephalosporines was found to be about 10% and over 20% to ciprofloxacin. K. pneumoniae isolates' resistance to third-generation cephalosporines was found to be more than 30% in 2001. P. aeruginosa resistance to all but a few antibiotics was found to be over 30% and multirresistance frequency was found to be 16% to 24%. CONCLUSION: The antimicrobial resistance rates found in the ICU of hospitals in Bogotá were higher than those reported in surveillance studies in the USA, Europe or other Latin-American cities.

Adolescent↗

PubMed2006

Advances in the therapy of chronic idiopathic myelofibrosis.

The molecular basis of chronic idiopathic myelofibrosis (CIMF) has remained elusive, thus hampering the development of effective targeted therapies. However, significant progress regarding the molecular mechanisms involved in the pathogenes is of this disease has been made in recent years that will likely provide ample opportunity for the investigation of novel therapeutic approaches. At the fore front of these advances is the discovery that 35%-55% of patients with CIMF harbor mutations in the Janus kinase 2 tyrosine kinase gene. Until very recently, the management of patients with CIMF involved the use of supportive measures, including growth factors, transfusions, or interferon, and the administration of cyto-reductive agents, such as hydroxyurea and anagrelide. However, several trials have demonstrated the efficacy of antiangiogenic agents alone or in combination with corticosteroids. In addition, the use of reduced-intensity conditioning allogeneic stem cell transplantation has resulted in prolonged survival and lower transplant-related mortality.

Antineoplastic Agents↗

PubMed2006

Targeting ABL and SRC kinases in chronic myeloid leukemia: experience with dasatinib.

Mutations within the ABL kinase domain and overexpression of SRC family kinases have been identified among the known mechanisms of resistance to imatinib in chronic myeloid leukemia (CML). The development of agents with dual inhibitory activity against SRC and ABL kinases is one approach to overcome imatinib resistance. One such agent, dasatinib (formerly BMS-354825), is approximately 300-fold more potent against BCR-ABL than imatinib, and is active against all tested ABL mutant isoforms, except for T315I. Dasatinib has demonstrated high efficacy in Phase I and II studies in patients with CML following failure of imatinib therapy. Studies exploring the efficacy of dasatinib as front-line therapy in patients with BCR-ABL-expressing hematologic malignancies are underway.

Benzamides↗

PubMed2006

Kinase inhibitors in chronic myelogenous leukemia.

The Bcr-Abl tyrosine kinase inhibitor imatinib mesylate launched the era of molecular targeted therapy and constitutes a milestone in oncology history. However, despite impressive cytogenetic response rates achieved with this agent in patients with chronic myelogenous leukemia (CML) in chronic phase, those with advanced-stage CML frequently obtain more modest responses that are in many instances of short duration. Several mechanisms of resistance to imatinib have been described among patients that develop clinical resistance to imatinib. Point mutations in the Bcr-Abl kinase domain that impair the ability of imatinib to inhibit the kinase activity represent the leading cause of resistance. Several approaches are being pursued to overcome these mutations. In addition, many other protein kinases implicated in signaling transduction downstream Bcr-Abl play critical roles in the pathogenesis of CML, thus representing potential therapeutic targets. Multiple compounds are being screened to identify inhibitors of these kinases. This article focuses on the current state of development of new kinase inhibitors for the therapy of CML.

Aniline Compounds↗

PubMed2005

Pharmacodynamics of cytarabine alone and in combination with 7-hydroxystaurosporine (UCN-01) in AML blasts in vitro and during a clinical trial.

Chk1 and Akt signaling facilitate survival of cells treated with nucleoside analogues. Activation of Chk1 in response to cytarabine (ara-C) induced an S-phase checkpoint characterized by the inhibition of Cdk2, cell cycle arrest, no change in constitutively active Akt, or low-stress kinase signaling in ML-1 cells. However, inhibition of Chk1 by UCN-01 in S-phase-arrested cells resulted in an abrogation of the checkpoint, inhibition of Akt, activation of JNK, and a rapid induction of apoptosis. Similarly, primary acute myelogenous leukemia (AML) blasts exposed to ara-C and UCN-01 demonstrated a selective loss in cloning potential when compared with normal progenitors. Therefore, we evaluated a pilot clinical trial of ara-C in combination with UCN-01 in patients with relapsed AML. Blasts from some patients demonstrated a previously activated Chk1-Cdk2 DNA damage response pathway that decreased during therapy. Constitutively phosphorylated Akt kinase declined on addition of UCN-01 to the ara-C infusion, an action accompanied by an activation of JNK and reduction in absolute AML blast counts. Thus, use of UCN-01 in combination with ara-C decreases Chk1 phosphorylation, inhibits the Akt survival pathway, and activates JNK during the course of therapy, offering a rationale for the cytotoxic action of this combination during AML treatment.

Adolescent↗

PubMed2005

Phase I study of cloretazine (VNP40101M), a novel sulfonylhydrazine alkylating agent, combined with cytarabine in patients with refractory leukemia.

PURPOSE: Cloretazine (VNP40101M) is a novel sulfonylhydrazine alkylating agent with significant antileukemia activity. A phase I study of cloretazine combined with cytarabine (1-beta-d-arabinofuranosylcytosine, ara-C) was conducted in patients with refractory disease. DESIGN: Ara-C was given i.v. at a fixed dose of 1.5 gm/m(2)/d by continuous infusion for 4 days (patients ages <65 years at time of diagnosis) or 3 days (patients ages > or =65 years). Cloretazine was given i.v. over 15 to 60 minutes on day 2 at a starting dose of 200 mg/m(2), with escalation in 100 mg/m(2) increments in cohorts of three to six patients until a maximum tolerated dose was established. The DNA repair enzyme O(6)-alkylguanine DNA alkyltransferase (AGT) was measured at baseline. RESULTS: Forty patients, including 32 with acute myeloid leukemia, received 47 courses of treatment. Complete responses were seen at cloretazine dose levels of > or =400 mg/m(2) in 10 of 37 (27%) evaluable patients, and in this patient subset, AGT activity was significantly lower in patients that responded to treatment than in patients who did not (P < or = 0.027). Dose-limiting toxicities (gastrointestinal and myelosuppression) were seen with 500 and 600 mg/m(2) of cloretazine combined with the 4-day ara-C schedule but not seen with the 3-day schedule. CONCLUSION: The recommended cloretazine dose schedule for future studies is 600 mg/m(2) combined with 1.5 gm/m(2)/d continuous infusion of ara-C for 3 days. The cloretazine and ara-C regimen has significant antileukemic activity. AGT activity may be a predictor of response to cloretazine.

Adult↗

PubMed2005

Sudden blastic transformation in patients with chronic myeloid leukemia treated with imatinib mesylate.

Sudden blastic transformation (SBT) has been reported in 0.5% to 2.5% of patients treated with interferon-alpha (IFN-alpha) during the first 3 years of therapy. Imatinib is now standard therapy for patients with chronic myeloid leukemia in chronic phase. We investigated the occurrence of SBT among patients treated with imatinib. Among 541 patients treated with imatinib in chronic phase, 23 developed blast phase, which was of sudden onset (ie, occurring in patients previously in complete cytogenetic remission) in 4 patients (17%; 0.7% of the total), 2 lymphoid and 2 myeloid. Patients with SBT were found to have low-risk features more often at the time of presentation and had achieved optimal response with imatinib. Three of the 4 patients underwent allogeneic stem cell transplantation and achieved a molecular remission. SBT is still a rare event, probably less common than that observed with IFN-alpha therapy. Continuous monitoring of patients treated with imatinib is mandatory.

Adult↗

PubMed2005

AMN107, a novel aminopyrimidine inhibitor of p190 Bcr-Abl activation and of in vitro proliferation of Philadelphia-positive acute lymphoblastic leukemia cells.

BACKGROUND: Previous studies have shown that patients with Bcr-Abl-positive acute lymphoblastic leukemia (ALL) either have primary disease that is refractory to imatinib mesylate or develop disease recurrence after an initial response. METHODS: The authors investigated the effects of a newly designed Bcr-Abl inhibitor, AMN107, by comparing its in vitro inhibitory potency on p190 Bcr-Abl ALL cell lines with that of imatinib. RESULTS: In two Philadelphia (Ph)-positive ALL cell lines, AMN107 was found to be 30-40 times more potent than imatinib in inhibiting cellular proliferation. AMN107 was also more effective than imatinib in inhibiting phosphorylation of p190 Bcr-Abl tyrosine kinase in cell lines and primary ALL cells. The inhibition of cellular proliferation was associated with the induction of apoptosis in only one of the cell lines. No activity was observed in cell lines lacking the BCR-ABL genotype. CONCLUSIONS: The results of the current study suggest the superior potency of AMN107 compared with imatinib in Ph-positive ALL and support clinical trials of AMN107 in patients with Ph-positive ALL.

Antineoplastic Agents↗

PubMed2005

Phase 1 study of ABT-751, a novel microtubule inhibitor, in patients with refractory hematologic malignancies.

PURPOSE: ABT-751 is an oral antimitotic agent that binds to the colchicine site on beta-tubulin. A phase 1 study was conducted to determine the maximum tolerated dose and toxicities of ABT-751 in patients with advanced myelodysplastic syndrome and relapsed or refractory acute leukemias. STUDY DESIGN: Thirty-two patients were treated: nine with 100 (n = 3), 125 (n = 3), or 150 mg/m(2) (n = 3) of ABT-751 given orally once daily for 7 days every 3 weeks and 23 with 75 (n = 3), 100 (n = 3), 125 (n = 5), 150 (n = 5), 175 (n = 3), or 200 mg/m(2) (n = 4) of ABT-751 given orally once daily for 21 days every 4 weeks. Consenting patients had pharmacogenetic sampling and enumeration of circulating endothelial cells (CEC). RESULTS: Dose-limiting toxicity consisted of ileus in one patient at 200 mg/m(2), with a subsequent patient developing grade 2 constipation at the same dose level. One patient with relapsed acute myelogenous leukemia achieved a complete remission that was sustained for 2 months. Four other patients had transient hematologic improvements, consisting of a decrease in peripheral blood blasts and improvements in platelet counts. CEC number was reduced in three patients with a concomitant reduction in peripheral blasts. A previously undescribed nonsynonymous single nucleotide polymorphism, encoding Ala(185)Thr, was identified in exon 4 of the beta-tubulin gene, TUBB, in three other patients. The recommended phase 2 dose in hematologic malignancies is 175 mg/m(2) daily orally for 21 days every 4 weeks. CONCLUSION: Further assessment of ABT-751, especially in combination with other agents, in patients with acute leukemias is warranted.

AC133 Antigen↗

PubMed2005

New targeted approaches in chronic myeloid leukemia.

The treatment of chronic myeloid leukemia has changed dramatically in the last few years. Stem-cell transplantation and the use of interferon alfa had already offered the possibility of complete and durable cytogenetic responses, improving the survival over that expected with conventional chemotherapy. The introduction of imatinib mesylate has started the era of molecular therapy with remarkable results including complete cytogenetic responses in up to 90% of patients and major molecular responses in most. However, some patients, particularly those treated in the advanced stages, may develop resistance to imatinib. Thus there has been interest in developing new agents that would not only help patients for whom imatinib is ineffective or intolerable, but that could also be combined with the intention of eliminating all evidence of disease. Several approaches are being pursued. These include new and more potent tyrosine kinase inhibitors that may not be affected by the most common mutations seen in the clinic. Some of these agents also inhibit Src-related kinases that may play a role in the development of resistance to imatinib. Other agents are directed at downstream or alternative pathways in leukemic cells, exploring potential synergy with imatinib. Another approach is to pursue an immune modulation that might eliminate small amounts of residual disease. Many of these agents are already showing promising results in the clinic. This manuscript reviews some of these agents, particularly those for which clinical data are already available.

Benzamides↗

PubMed2005

Phase I evaluation of a 40-kDa branched-chain long-acting pegylated IFN-alpha-2a with and without cytarabine in patients with chronic myelogenous leukemia.

PURPOSE: Pegasys (PEG-IFN) is a modified form of recombinant human IFN-alpha-2a in which IFN-alpha is attached to a branched methoxypolyethylene glycol (PEG) moiety of large molecular weight (40 kDa). Such molecular modification results in sustained absorption after s.c. drug administration and a prolonged half-life. A phase I study of PEG-IFN was conducted in patients with chronic myelogenous leukemia (CML) who were previously treated with IFN-alpha to evaluate the effect of sustained exposure to IFN on patients with CML. EXPERIMENTAL DESIGN: Twenty-seven patients with long-term or IFN-refractory CML were enrolled in cohorts of three or six patients. PEG-IFN was given once weekly by s.c. injections starting at a dose of 270 microg/wk to a maximum dose of 630 microg/wk. Sixteen additional patients were treated with escalating doses of PEG-IFN ranging from 450 to 540 microg/wk in combination with two different schedules of low-dose cytarabine (1-beta-D-arabinofuranosylcytosine, ara-C). Serial venous blood samples were collected to evaluate the pharmacokinetic and pharmacodynamic characteristics of PEG-IFN in these patients. RESULTS: The dose-limiting toxicity (DLT) as defined by the protocol was not achieved at the highest dose tested of 630 mug/wk. With the addition of ara-C, the DLT was reached at 540 microg/wk. The safety profile was similar to that of unmodified IFNs. Of 27 patients treated with PEG-IFN, 14 (52%) achieved or maintained a complete hematologic response and three (11%) achieved a complete cytogenetic response. Among 16 patients treated with the combination of PEG-IFN and ara-C, 11 (69%) achieved or maintained complete hematologic remission and two (13%) achieved complete cytogenetic remission. The mean serum peak concentration (C(max)) of PEG-IFN increased from 9.4 to 28 ng/mL as the dose increased from 270 to 450 microg/wk, with no further increases in C(max) at higher dose levels. Serum concentration reached peak value starting about 48 hours after drug administration and was maintained at close to peak value throughout the dosing interval. The mean +/- SD area under the serum concentration-time curve (AUC) calculated after the first dose also increased from 1,022 +/- 694 to 3,343 +/- 2,728 ng hour/mL as dose was increased from 270 to 450 microg/wk, showing a dose-related increase in systemic exposure of PEG-IFN. As with C(max), the AUC did not increase at higher dose levels. The maximum induction (E(max)) of neopterin, the surrogate marker of the pharmacodynamic activity of PEG-IFN, increased from 120% to 361% over baseline values as the dose was increased from 270 to 540 microg/wk. On the once-weekly multiple dosing schedule, both the PEG-IFN and neopterin concentration seemed to reach steady state by week 5 and the steady-state values were maintained with chronic dosing over 6 months. CONCLUSION: Pegasys provided a significant advantage over standard IFN-alpha by enabling once-weekly dosing while maintaining acceptable safety, tolerability, and activity profiles. This branched 40-kDa PEG-IFN was well tolerated both as a monotherapy as well as in combination with ara-C. Demonstration of its sustained exposure, pharmacodynamic activity, hematologic response, and evidence of cytogenetic response in several patients in this limited study with either IFN-refractory or INF-intolerant patients provides a promise for further investigation in combination with new agents like imatinib.

Adult↗

PubMed2005

Adult acute megakaryocytic leukemia: an analysis of 37 patients treated at M.D. Anderson Cancer Center.

To characterize acute megakaryocytic leukemia (FAB M7 AML), we identified 37 patients with M7 AML treated at M.D. Anderson Cancer Center between 1987 and 2003 and compared them with 1800 patients with non-M7, non-M3 AML treated during the same period. The median age of the M7 AML group was 56 years (range, 21-78 years); 22 patients (59%) had an antecedent hematologic disorder or myelodysplastic syndrome or both, and 7 patients (19%) had previously received chemotherapy for other malignancies. Extensive bone marrow fibrosis was found in 23 patients (62%). Poor cytogenetic characteristics were observed in 49% of patients with M7 AML versus 33% of others (P < .001). Complete remission rates were 43% with M7 AML and 57% with non-M7 AML (P = .089). Median overall survival (OS) was 23 and 38 weeks, respectively (P = .006). Median disease-free survivals were 23 versus 52 weeks, respectively (P < .001). By multivariate analysis, M7 AML was an independent adverse prognostic factor for OS, independent of other factors including cytogenetic abnormalities (hazard ratio 1.51, P = .049). These results confirm the poor prognosis of M7 AML and indicate that other biologic characteristics beyond cytogenetic abnormalities likely play a role in this disease.

Adult↗