Biomedical subjects

Elias Jabbour

Publications and source records attributed to Elias Jabbour.

16 recordsLinked to original sources

PubMed2007

Update of the decitabine experience in higher risk myelodysplastic syndrome and analysis of prognostic factors associated with outcome.

BACKGROUND: Therapy for patients with myelodysplastic syndrome (MDS) with hypomethylating agents, like decitabine and 5-azacitidine, has produced favorable results. In this study, the authors update their experience with decitabine in patients with MDS and analyze the cytogenetic response patterns and prognostic factors associated with decitabine therapy. METHODS: One hundred fifteen patients with higher risk MDS who received treatment with decitabine were reviewed. Patients received decitabine 100 mg/m(2) per course every 4 weeks in 3 different schedules: 1) 20 mg/m(2) intravenously daily x 5, 2) 20 mg/m(2) subcutaneously daily x 5, and 3) 10 mg/m(2) intravenously daily x 10. Decitabine was given for a median of >or=7 courses (range, 1-23 courses). RESULTS: Overall, 80 patients (70%) achieved a response according to the modified International Working Group criteria (IWG): complete response (CR), 40 patients (35%); partial response, 2 patients (2%); bone marrow CR with or without other hematologic improvements (HI), 26 patients (23%); and other HI, 12 patients (10%). Cytopenias were improved in 50% of patients. The median remission duration was 20 months, and the median survival was 22 months. Mortality was 3% at 6 weeks and 7% at 3 months. In a multivariate analysis, poor prognostic factors for achieving IWG CR were MDS (vs chronic myelomonocytic leukemia), longer duration of MDS, and prior MDS therapy. For survival, independent adverse prognostic factors were chromosome 5 and/or 7 abnormalities, older age, and prior MDS therapy (excluding growth factors). CONCLUSIONS: The longer term experience with decitabine in MDS was favorable. Pretreatment prognostic factors may predict the outcome of patients who receive decitabine therapy for MDS.

Aged↗

PubMed2007

Neurologic complications associated with intrathecal liposomal cytarabine given prophylactically in combination with high-dose methotrexate and cytarabine to patients with acute lymphocytic leukemia.

Central nervous system (CNS) prophylaxis has led to a significant improvement in the outcome of patients with acute lymphocytic leukemia (ALL). Liposomal cytarabine (Enzon Pharmaceuticals, Piscataway, NJ; Skye Pharma, San Diego, CA), an intrathecal (IT) preparation of cytarabine with a prolonged half-life, has been shown to be safe and effective in the treatment of neoplastic meningitis. Liposomal cytarabine was given for CNS prophylaxis to 31 patients with newly diagnosed ALL. All patients were treated concurrently with hyper-CVAD chemotherapy (fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) including high-dose methotrexate (MTX) and cytarabine on alternating courses. Liposomal cytarabine 50 mg was given intrathecally on days 2 and 15 of hyper-CVAD and day 10 of high-dose MTX and cytarabine courses until completion of either 3, 6, or 10 IT treatments, depending on risk for CNS disease. Five patients (16%) experienced serious unexpected neurotoxicity, including seizures, papilledema, cauda equina syndrome (n = 2), and encephalitis after a median of 4 IT administrations of liposomal cytarabine. Toxicities usually manifested after the MTX and cytarabine courses. One patient died with progressive encephalitis. After a median follow-up of 7 months, no isolated CNS relapses have been observed. Liposomal cytarabine given via intrathecal route concomitantly with systemic chemotherapy that crosses the blood-brain barrier such as high-dose MTX and cytarabine can result in significant neurotoxicity.

Adult↗

PubMed2006

Activity of 9-nitro-camptothecin, an oral topoisomerase I inhibitor, in myelodysplastic syndrome and chronic myelomonocytic leukemia.

BACKGROUND: Topoisomerase I inhibitors, like topotecan, have activity in myelodysplastic syndrome (MDS) and chronic myelomonocytic leukemia (CMML). 9-Nitro-camptothecin (9-NC) is a new oral topoisomerase inhibitor with a good safety profile. The aims of the current study were to evaluate the activity and safety of 9-NC in MDS and CMML. METHODS: Adults with a diagnosis of MDS (n = 12) and CMML (n = 32) received 9-NC 2 mg/m(2) orally daily 5 days a week, every 4 to 6 weeks. RESULTS: Overall, 5 (11%) patients achieved complete response (CR), 7 (16%) had a partial response (PR), and 6 (14%) had hematologic improvement (HI), for an overall response rate of 41%. The response rate was similar in MDS and CMML. Severe (Grade 3-4) side effects included nausea and vomiting (7%), diarrhea (18%), other gastrointestinal toxicities (5%), and genitourinary toxicities (12%). CONCLUSIONS: 9-NC is active in MDS and CMML. The paucity of available therapies in CMML makes 9-NC a good candidate for further studies as a single agent, or in combination with decitabine, 5-azacitidine or cytarabine.

Administration, Oral↗

PubMed2006

Phase 1/2 study of the combination of 5-aza-2'-deoxycytidine with valproic acid in patients with leukemia.

We conducted a phase 1/2 study of the combination of 5-aza-2'-deoxycytidine (decitabine) and the histone deacetylase inhibitor valproic acid (VPA) in patients with advanced leukemia, including older untreated patients. A group of 54 patients were treated with a fixed dose of decitabine (15 mg/m(2) by IV daily for 10 days) administered concomitantly with escalating doses of VPA orally for 10 days. A 50 mg/kg daily dose of VPA was found to be safe. Twelve (22%) patients had objective response, including 10 (19%) complete remissions (CRs), and 2 (3%) CRs with incomplete platelet recovery (CRp). Among 10 elderly patients with acute myelogenous leukemia or myelodysplastic syndrome, 5 (50%) had a response (4CRs, 1CRp's). Induction mortality was observed in 1 (2%) patient. Major cytogenetic response was documented in 6 of 8 responders. Remission duration was 7.2 months (range, 1.3-12.6+ months). Overall survival was 15.3 months (range, 4.6-20.2+ months) in responders. Transient DNA hypomethylation and global histone H3 and H4 acetylation were induced, and were associated with p15 reactivation. Patients with lower pretreatment levels of p15 methylation had a significantly higher response rate. In summary, this combination of epigenetic therapy in leukemia was safe and active, and was associated with transient reversal of aberrant epigenetic marks.

Acetylation↗

PubMed2006

Allogeneic stem cell transplantation for patients with chronic myeloid leukemia and acute lymphocytic leukemia after Bcr-Abl kinase mutation-related imatinib failure.

Resistance to imatinib mesylate is an emerging problem in the treatment of chronic myeloid leukemia (CML), often associated with point mutations in the Bcr-Abl kinase domain. Outcome of patients with such mutations after allogeneic stem cell transplantation (Allo-SCT) is unknown. Ten imatinib-resistant patients with Bcr-Abl kinase mutations received a transplant: 9 had CML (3 in chronic phase, 4 in accelerated phase, and 2 in blast phase) and 1 had Philadelphia-positive acute lymphocytic leukemia (ALL). Patients harbored 9 different protein kinase mutations (T315I mutation, n = 2). Preparative regimens were ablative (n = 7) and nonablative (n = 3). All patients engrafted; there were no treatment-related deaths. Disease response was complete molecular (CMR; n = 7), major molecular (n = 2), and no response (n = 1). Three patients (mutations Q252H, E255K, and T315I) died of relapse after Allo-SCT. Seven patients are alive (6 in CMR) for a median of 19 months. Allo-SCT remains an important salvage option for patients who develop resistance to imatinib through Bcr-Abl mutations.

Adult↗

PubMed2006

Results of intensive chemotherapy in 998 patients age 65 years or older with acute myeloid leukemia or high-risk myelodysplastic syndrome: predictive prognostic models for outcome.

BACKGROUND: Elderly patients (age > or = 65 years) with acute myeloid leukemia (AML) generally have a poor prognosis. AML-type therapy results are often derived from studies in younger patients and may not apply to elderly AML. Many investigators and oncologists advocate, at times, only supportive care or frontline single agents, Phase I-II studies, low-intensity regimens, or 'targeted' therapies. However, baseline expectations for outcomes of elderly AML with 'standard' AML-type therapy are not well defined. The aim was to develop prognostic models for complete response (CR), induction (8-week) mortality, and survival rates in elderly AML, which would be used to advise oncologists and patients of expectations with standard AML type therapy, and to establish baseline therapy results against which novel strategies would be evaluated. METHODS: A total of 998 patients age > or = 65 years with AML or high-risk myelodysplastic syndrome (> 10% blasts) treated with intensive chemotherapy between 1980 and 2004 were analyzed. Univariate and multivariate analyses of prognostic factors associated with CR, induction (8-week) mortality, and survival used standard methods. RESULTS: The overall CR rate was 45% and induction mortality 29%. Multivariate analysis of prognostic factors identified consistent independent poor prognostic factors for CR, 8-week mortality, and survival. These included age > or = 75 years, unfavorable karyotypes (often complex), poor performance (3-4 ECOG [Eastern Cooperative Oncology Group]), longer duration of antecedent hematologic disorder, treatment outside the laminar airflow room, and abnormal organ functions. Patients could be divided into: 1) a favorable group (about 20% of patients) with expected CR rates above 60%, induction mortality rates of 10%, and 1-year survival rates above 50%; 2) an intermediate group (about 50-55% of patients) with expected CR rates of 50%, induction mortality rates of 30%, and 1-year survival rates of 30%; and 3) an unfavorable risk group (about 25-30% of patients) with expected CR rates of less than 20%, induction mortality rates above 50%, and 1-year survival rates of less than 10%. CONCLUSIONS: Prognostic models, based on standard readily available baseline characteristics, were developed for elderly patients with AML, which may assist in therapeutic and investigational decisions. These predictive models, based on a retrospective analysis, will require validation in independent study groups.

Age Factors↗

PubMed2006

Dasatinib.

Explore the source record for details and available documents.

Administration, Oral↗

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

Validation of the European Prognostic Index for younger adult patients with acute myeloid leukaemia in first relapse.

In order to validate the European Prognostic Index (EPI) for patients <or=60 years with acute myeloid leukaemia in first relapse, a cohort of 599 such patients, treated between 1980 and 2004 at the MD Anderson Cancer Center, were assessed using this prognostic index. Three risk groups were defined: favourable, 76 patients (13%) [Overall survival (OS), 64% at 1 year, 22% at 5 years]; intermediate, 137 patients (23%) (OS, 38% at 1 year, 12% at 5 years); and poor, 386 patients (64%) (OS, 17% at 1 year 6% at 5 years). The EPI is reproducible and useful.

Acute Disease↗

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

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↗

PubMed2005

2-Chlorodeoxyadenosine and cytarabine combination therapy for idiopathic hypereosinophilic syndrome.

BACKGROUND: Hypereosinophilic syndrome (HES) is a rare, disabling, and incurable disease. In this study, a combination of 2-chlorodeoxyadenosine (2-CdA) and cytosine arabinoside (ara-C) chemotherapy was evaluated in patients with HES. METHODS: Nine patients with HES were treated with ara-C (1 g/m(2)) given intravenously over 2 hours at 0 hours, 48 hours, 72 hours, 96 hours, and 120 hours; and 2-CdA (12 mg/m(2) per day) was given as a continuous intravenous infusion over 5 days starting at 24 hours. A second course of the same therapy was administered in patients who had a response. RESULTS: All patients had signs and symptoms of end-organ involvement. The median time from diagnosis to therapy was 25 months. Seven patients had received prior therapies. Five patients (55%) achieved a complete remission (CR), 1 after receiving 2 courses of therapy. Elimination of eosinophilia was accompanied by the resolution of symptoms. The median disease-free survival and overall survival after the diagnosis for patients who achieved CR was 26 months and 44 months, respectively. Treatment was tolerated well. Febrile neutropenia occurred in 28% of the 14 courses that were given. The median time to recovery from neutropenia and thrombocytopenia was 17 days and 39 days, respectively. CONCLUSIONS: The combined 2-CdA and ara-C chemotherapy regimen had activity in patients with HES.

Adolescent↗

PubMed2005

Interferon alpha therapy for patients with essential thrombocythemia: final results of a phase II study initiated in 1986.

BACKGROUND: In 1986, a Phase II trial of recombinant interferon-alpha (IFN-alpha) was initiated as therapy for patients with essential thrombocythemia (ET). METHODS: Patients were treated with subcutaneous IFN-alpha at a dose of 5 x 10(6) units/m(2) daily. In responding patients, the therapy lasted at least 3 years. RESULTS: Twenty-three patients (14 females and 9 males; median age, 41 years; age range, 20-63 years) with a median platelet count of 1350 x 10(9)/L were treated. After a median follow-up of 174 months (14.5 years), 15 of 20 evaluable patients (75%) responded, including 14 patients who achieved a complete hematologic response (CHR) (6 of them with bone marrow remission) and 1 patient who demonstrated a partial response. The median time to response was 6 months (range, 0.5-36 months), and the median response duration was 48 months (range, 5-114 months). Seven patients who achieved a CHR and were taken off therapy after they completed 3 years of maintenance therapy sustained their response for a median of 28 months. No symptoms or signs of thrombosis or hemorrhage were observed in responding patients. Eleven of 14 patients (78%) who achieved a CHR developed a recurrence, and 2 of 5 patients with recurrences who were rechallenged with IFN-alpha achieved a second response. The treatment was tolerated relatively well. CONCLUSIONS: IFN-alpha was safe and effective therapy for patients with ET, and the ability of IFN-alpha to reverse disease pathology and possibly modify the clinical course of patients with ET warrants its investigation in larger, prospective trials.

Adult↗

PubMed2005

Clinical experience with decitabine in North American patients with myelodysplastic syndrome.

Recent evidence demonstrates that epigenetic silencing of genes is associated with myelodysplasia and that a worse prognosis may be correlated with hypermethylation of certain genes, such as the cyclin-dependent kinase inhibitor p15. 5-Aza-2'-deoxycytidine (decitabine, DAC) is a nucleoside analog, which, at low doses, acts as a hypomethylating agent and is fivefold to tenfold more active than 5-azacytidine (azacitidine, Vidaza)--currently the only approved drug for treatment of myelodysplastic syndrome (MDS). Clinical studies have demonstrated that decitabine has activity in patients with MDS. Preliminary results of a phase III multicenter North American trial comparing low-dose decitabine to supportive care verified that therapy with decitabine resulted in higher response rates, improved quality of life, and prolonged time to leukemic transformation and/or death. However, further elucidation of its mechanism of action is required, as clinical response to decitabine does not correlate with demethylation of the p15 gene promoter or the repetitive DNA element LINE. Decitabine appears to upregulate both hypermethylated and nonmethylated genes. Ongoing studies aim to determine the optimal dose, schedule, and route of administration of decitabine, and to evaluate whether efficacy can be improved by using it in combination with other agents, such as histone deacetylase inhibitors.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2004

Clinical activity of farnesyl transferase inhibitors in hematologic malignancies: possible mechanisms of action.

Farnesyl transferase inhibitors (FTIs) are a novel class of anti-cancer agents that competitively inhibit farnesyl protein transferase (FTase). Initially developed to inhibit the prenylation necessary for Ras activation, their mechanism of action seems to be more complex, involving other proteins unrelated to Ras. FTIs have been developed and tested across a wide range of human cancers. At least 3 agents within this family have been investigated in hematologic malignancies. These are tipifarnib (R115777, Zarnestra), lonafarnib (SCH66336, Sarasar), both of which are orally administered, and BMS-214662, which is given intravenously. Preliminary results from clinical trials demonstrate enzyme target inhibition, a favorable toxicity profile and promising efficacy. Ongoing studies will better determine their mechanism of action and the role of combination with other agents, defining their place in the therapeutic arsenal of hematologic disorders.

Alkyl and Aryl Transferases↗