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Moshe Talpaz

Publications and source records attributed to Moshe Talpaz.

At least 73 records · Page 4Linked to original sources
PubMed2003

Philadelphia chromosome-positive leukemias: from basic mechanisms to molecular therapeutics.

The Philadelphia chromosome translocation (t(9;22)) results in the molecular juxtaposition of two genes, BCR and ABL, to form an aberrant BCR-ABL gene on chromosome 22. BCR-ABL is critical to the pathogenesis of chronic myelogenous leukemia and a subset of acute leukemias. The chimeric Bcr-Abl protein has constitutively elevated tyrosine phosphokinase activity. This abnormal enzymatic activation is critical to the oncogenic potential of Bcr-Abl. Initially, protein kinases were thought to be poor therapeutic targets because of their ubiquitous nature and crucial role in many normal physiologic processes. However, the advent of imatinib mesylate (Gleevec, Novartis Pharmaceuticals, Basel, Switzerland), formerly known as STI571 and CGP57148B, demonstrated that designer kinase inhibitors could be specific. This agent has shown striking activity in chronic myelogenous leukemia. It also inhibits phosphorylation of Kit (stem-cell factor receptor) and platelet-derived growth factor receptor. In addition, it has shown similar impressive responses, with little host toxicity, in gastrointestinal stromal tumors, which harbor activating Kit mutations, and in tumors with activated platelet-derived growth factor receptor. The studies of imatinib mesylate provide proof-of-principle for using aberrant kinases as a therapeutic target and are a model for the promise of molecular therapeutics. This paper reviews the current knowledge on the function of Bcr-Abl and its normal counterparts (Bcr and Abl), as well as the impact of this knowledge on the development of a remarkably successful targeted therapy approach.

Animals↗
PubMed2003

Prediction of initial cytogenetic response for subsequent major and complete cytogenetic response to imatinib mesylate therapy in patients with Philadelphia chromosome-positive chronic myelogenous leukemia.

BACKGROUND: Obtaining a major (Philadelphia chromosome [Ph] of < 35%) or a complete cytogenetic response (Ph of 0%) has been associated with excellent long-term survival. Cytogenetic response may continue to improve with therapy. Because early allogeneic stem cell transplantation (SCT) may be associated with a better outcome, early parameters predicting for subsequent cytogenetic responses would optimize the treatment decision-making. METHODS: The current study was performed to analyze whether early cytogenetic responses may be predictive of later major or complete cytogenetic responses to imatinib mesylate therapy in patients with Ph-positive chronic myelogenous leukemia (CML). RESULTS: Two hundred sixty-one patients with Ph-positive, chronic-phase CML after failure with interferon therapy who were treated with imatinib mesylate therapy were analyzed. A persistence of 100% Ph-positive cells after > or = 6 months of imatinib mesylate therapy was associated with a major cytogenetic response rate of 9-13% and a complete cytogenetic response rate of 0-4%. However, a minor cytogenetic response after 3-12 months of therapy still was associated with high rates of major (68-83%) or complete (35-54%) cytogenetic response rates. CONCLUSIONS: Patients with Ph-positive, chronic-phase CML who have persistent 100% Ph-positive disease after > or = 6 months of imatinib mesylate therapy may be offered allogeneic SCT or considered for alternative investigational therapies.

Benzamides↗
PubMed2003

Resveratrol blocks interleukin-1beta-induced activation of the nuclear transcription factor NF-kappaB, inhibits proliferation, causes S-phase arrest, and induces apoptosis of acute myeloid leukemia cells.

Resveratrol, an edible polyphenolic stilbene, has been reported to possess substantial antileukemic activities in different leukemia cell lines. We investigated whether resveratrol is active against fresh acute myeloid leukemia (AML) cells and its mechanism of action. Because interleukin 1beta(IL-1beta) plays a key role in proliferation of AML cells, we first tested the effect of resveratrol on the AML cell lines OCIM2 and OCI/AML3, both of which produce IL-1beta and proliferate in response to it. Resveratrol inhibited proliferation of both cell lines in a dose-dependent fashion (5-75 microM) by arresting the cells at S phase, thus preventing their progression through the cell cycle; IL-1beta partially reversed this inhibitory effect. Resveratrol significantly reduced production of IL-1beta in OCIM2 cells. It also suppressed the IL-1beta-induced activation of transcription factor nuclear factor kappaB (NF-kappaB), which modulates an array of signals controlling cellular survival, proliferation, and cytokine production. Indeed, incubation of OCIM2 cells with resveratrol resulted in apoptotic cell death. Because caspase inhibitors Ac-DEVD-CHO or z-DEVD-FMK partially reversed the antiproliferative effect of resveratrol, we tested its effect on the caspase pathway and found that resveratrol induced the activation of the cysteine protease caspase 3 and subsequent cleavage of the DNA repair enzyme poly (adenosine diphosphate [ADP]-ribose) polymerase. Finally, resveratrol suppressed colony-forming cell proliferation of fresh AML marrow cells from 5 patients with newly diagnosed AML in a dose-dependent fashion. Taken together, our data showing that resveratrol is an effective in vitro inhibitor of AML cells suggest that this compound may have a role in future therapies for AML.

Acute Disease↗
PubMed2003

Granulocyte-macrophage colony-stimulating factor (GM-CSF) induces antiapoptotic and proapoptotic signals in acute myeloid leukemia.

High levels of cytokines are associated with a poor prognosis in acute myeloid leukemia (AML). However, cytokines may induce, on one hand, survival factor expression and cell proliferation and, on the other hand, expression of inhibitory signals such as up-regulation of suppressors of cytokine signaling (SOCS) and induce apoptotic cell death. Because blasts from patients with AML express high procaspase protein levels, we asked whether granulocyte-macrophage colony-stimulating factor (GM-CSF) enhances procaspase protein production in AML cells. In the GM-CSF-responsive OCIM2 AML cell line, GM-CSF induced signal transducer and activator of transcription 5 (Stat 5) phosphorylation, up-regulated cyclin D2, and stimulated cell cycle progression. Concurrently, GM-CSF stimulated expression of SOCS-2 and -3 and of procaspases 2 and 3 and induced caspase 3 activation, poly(ADP[adenosine 5'-diphosphate]-ribose) polymerase (PARP) cleavage, and apoptotic cell death. The Janus kinase (Jak)-Stat inhibitor AG490 abrogated GM-CSF-induced expression of procaspase 3 and activation of caspase 3. Under the same conditions GM-CSF up-regulated production of BAX as well as Bcl-2, Bcl-XL, survivin, and XIAP. GM-CSF also increased procaspase 3 protein levels in OCI/AML3 and Mo7e cells, suggesting that this phenomenon is not restricted to a single leukemia cell line. Our data suggest that GM-CSF exerts a dual effect: it stimulates cell division but contemporaneously up-regulates Jak-Stat-dependent proapoptotic proteins. Up-regulation of procaspase levels in AML is thus a beacon for an ongoing growth-stimulatory signal.

Acute Disease↗
PubMed2003

Result of high-dose imatinib mesylate in patients with Philadelphia chromosome-positive chronic myeloid leukemia after failure of interferon-alpha.

Imatinib at 400 mg daily is effective in chronic-phase chronic myeloid leukemia (CML) after interferon failure, although only a few patients achieve a molecular remission. We investigated whether higher doses of imatinib may be more effective. Thirty-six patients with chronic-phase CML after failure on interferon-alpha were treated with 400 mg imatinib twice daily. Median time from diagnosis was 25 months (range, 10-135 months); 4 patients (11%) had clonal evolution. All 11 patients with active disease achieved complete hematologic response. Excluding patients with fewer than 35% Ph-positive metaphases before the start of therapy, 19 (90%) of 21 evaluable patients achieved a major cytogenetic response. Of 27 evaluable patients, 24 (89%) achieved a complete cytogenetic response. Quantitative polymerase chain reaction was performed in bone marrow every 3 months. Of 32 evaluable patients, 18 (56%) showed BCR-ABL/ABL percentage ratios lower than 0.045%, including 13 (41%) with undetectable levels. With a median follow-up of 15 months, all patients were alive in chronic phase. Toxicities were similar to those reported with standard dose; 71% of patients continue to receive 600 mg or more of imatinib daily. In conclusion, high-dose imatinib induces complete cytogenetic responses in most patients with chronic-phase CML after interferon failure. This is accompanied by a high rate of molecular remission.

Adult↗
PubMed2003

Complete cytogenetic and molecular responses to interferon-alpha-based therapy for chronic myelogenous leukemia are associated with excellent long-term prognosis.

BACKGROUND: Little is known regarding long-term prognosis among patients with Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia (CML) who achieve a complete cytogenetic response (0% Ph-positive cells) after treatment with interferon-alpha. METHODS: The authors analyzed 512 patients with Ph-positive, early chronic-phase CML who were treated with interferon-based therapies between 1981-1995 for the incidence and durability of complete cytogenetic response, and in relation to long-term prognosis. RESULTS: One hundred forty patients (27%) achieved a complete cytogenetic response. Their 10-year survival rate was 78%. At the time of last follow-up, 44 patients (31%, 9% of the total) were alive, 21 in first and 23 in second durable complete cytogenetic response (median, 127 months; range, 88-191 months); 39 patients had not received any therapy for a median of 50 months (range, 11-139 months). Analysis by reverse transcriptase-polymerase chain reaction in 78 patients during complete cytogenetic response showed 46 who had achieved at least 1 complete molecular response. Five of these 78 patients had died by the time of last follow-up, but only 2 had died of disease-specific causes. Recurrence rates were significantly lower and cytogenetic response durations were significantly longer among patients who achieved at least one complete molecular response. CONCLUSIONS: Achieving a complete cytogenetic or molecular response after therapy with interferon-alpha appears to be associated with excellent long-term prognosis. Approximately 10% of patients reportedly can achieve durable complete cytogenetic response, with or without continuation of interferon. This finding emphasizes the potential of long-term event-free survival in CML patients outside the context of allogeneic stem cell transplantation, which may be improved with new therapies such as imatinib mesylate.

Female↗
PubMed2003

Prognostic significance of cytogenetic clonal evolution in patients with chronic myelogenous leukemia on imatinib mesylate therapy.

Cytogenetic clonal evolution (CE) is a known poor prognostic factor in Philadelphia chromosome-positive chronic myelogenous leukemia (Ph-positive CML). However, its prognostic relevance in the era of imatinib therapy is unknown. We investigated the independent prognostic relevance of CE in 498 patients with Ph-positive CML treated with imatinib for chronic or accelerated phases. One hundred twenty-one patients had CE alone (n = 70) or with other accelerated phase criteria (n = 51). Patients were compared in 4 categories: chronic phase (n = 295), CE only (n = 70), accelerated phase without CE (n = 82), and accelerated phase with CE (n = 51). Statistical methods used established methodologies for univariate and multivariate analyses. In chronic and accelerated phases of CML, CE was not associated with significant differences in major or complete cytogenetic response rates, but it was an independent poor prognostic factor for survival by multivariate analyses in both chronic (P =.005) and accelerated phase (P =.03). Multivariate analyses conducted at the 3-month landmark (including the 3-month cytogenetic response) identified the lack of cytogenetic response at 3 months to be a stronger independent poor prognostic factor for survival than CE for both chronic (major cytogenetic response versus other) and accelerated phase (any cytogenetic response versus other). We conclude that cytogenetic CE is not an important factor for achieving major or complete cytogenetic response with imatinib mesylate therapy, but it is an independent poor prognostic factor for survival in both chronic and accelerated phases of CML. The 3-month cytogenetic response to imatinib mesylate refined the prognostic relevance of such studies in patients on imatinib mesylate therapy.

Age Factors↗
PubMed2003

BCR-ABL independence and LYN kinase overexpression in chronic myelogenous leukemia cells selected for resistance to STI571.

Clinical studies have shown that the tyrosine kinase inhibitor STI571 effectively controls BCR-ABL-positive chronic myelogenous leukemia (CML). However, disease progression while on STI571 therapy has been reported, suggesting de novo or intrinsic resistance to BCR-ABL-targeted therapy. To investigate possible mediators of acquired STI571 resistance, K562 cells resistant to 5 microM STI571 (K562-R) were cloned and compared to the parental cell population. K562-R cells had reduced BCR-ABL expression and limited activation of BCR-ABL signaling cascades (Stat 5, CrkL, MAPK). STI571 failed to activate caspase cascades or to suppress expression of survival genes (bcl-xL) in resistant cells. Gene sequencing and tyrosine kinase activity measurements demonstrated that K562-R cells retained wild-type and active BCR-ABL tyrosine kinase that was inhibitable by in vitro incubation with STI571, suggesting that BCR-ABL was not coupled to proliferation or survival of K562-R cells. The src-related kinase LYN was highly overexpressed and activated in K562-R cells, and its inhibition reduced proliferation and survival of K562-R cells while having limited effects of K562 cells. Specimens taken from patients with advanced CML that progressed on STI571 therapy also were analyzed for LYN kinase expression, and they were found to be elevated to a level similar to that of K562-R cells. Comparison of samples from patients taken prior to and following STI571 failure suggested that expression and/or activation of LYN/HCK occurs during disease progression. Together, these results suggest that acquired STI571 resistance may be associated with BCR-ABL independence and mediated in part through overexpression of other tyrosine kinases.

Benzamides↗
PubMed2003

Phase II study of troxacitabine, a novel dioxolane nucleoside analog, in patients with untreated or imatinib mesylate-resistant chronic myelogenous leukemia in blastic phase.

A phase II study of troxacitabine, a non-natural dioxolane nucleoside L-enantiomer, was conducted in patients with chronic myelogenous leukemia in blastic phase (CML-BP). Patients were untreated for BP, or treated with imatinib mesylate (IM) as sole prior therapy for BP. Troxacitabine was given as an intravenous infusion over 30 min daily for 5 days at a dose of 8.0 mg/m(2) per day. Thirty-one patients, 29 (93%) of whom had failed prior IM therapy, received 51 courses of therapy. Grade 3 or 4 toxicities included stomatitis (4%), hand-foot syndrome (18%), and skin rash (12%). Four patients (13%) responded. Troxacitabine-based combinations merit study in IM-resistant CML.

Adult↗
PubMed2003

Quantitative polymerase chain reaction monitoring of BCR-ABL during therapy with imatinib mesylate (STI571; gleevec) in chronic-phase chronic myelogenous leukemia.

PURPOSE: The purpose of our investigation was to evaluate the response and minimal residual disease by quantitative competitive PCR (QC-PCR) studies in patients with chronic myeloid leukemia (CML) treated with imatinib mesylate. EXPERIMENTAL DESIGN: One hundred eighty patients with Philadelphia chromosome (Ph)-positive chronic-phase CML after IFN-alpha failure, treated with imatinib mesylate, had 543 simultaneous cytogenetic and QC-PCR analyses at different times during their therapy. RESULTS: The median QC-PCR values [ratio-percentage of (BCR-ABL/ABL transcripts) x 100] for cytogenetic response categories were: no response (Ph, >90%), 36%; minor response (Ph, 35-90%), 22%; partial response (Ph, 1-34%), 7.3%; complete response (Ph, 0%), 0.89%. There was good correlation between cytogenetic and QC-PCR studies (P < 0.001; r = 0.92) and good concordance between QC-PCR values (>10%, 2-10%, and <2%) and cytogenetic response categories (none, minor, partial, complete) with a concordance rate of 66%, and major discordance of only 10%. Of 170 samples in complete cytogenetic response, 21% still had QC-PCR values of >10%, and 53% had QC-PCR values of <1%. There was excellent concordance between blood and marrow QC-PCR values (r = 0.965; P < 0.01; concordance rate, 88%; major discordance, 0%). No patient in complete cytogenetic response regardless of QC-PCR value has yet relapsed. At a median follow-up time of 26 months, higher QC-PCR values within each cytogenetic category at 3, 6, and 9 months have not been associated with a higher occurrence cytogenetic relapse or disease progression. However, the significance of this may become different with longer follow-up. CONCLUSION: QC-PCR studies provide a useful tool to monitor patients with CML on imatinib mesylate therapy.

Antineoplastic Agents↗
PubMed2003

Modulation of cellular signaling pathways: prospects for targeted therapy in hematological malignancies.

The high remission rates observed in patients with chronic myelogenous leukemia who receive Imatinib mesylate (Gleevec) indicate that targeted therapy for hematological malignancies is achievable. At the same time, progress in cellular biology over the past decade has resulted in a better understanding of the process of malignant transformation, a better classification of subtypes of each disease on the basis of molecular markers, and a better characterization of the molecular targets for drug development. These advances have already spawned the development of such effective agents as monoclonal antibodies and specific enzyme inhibitors. This review attempts to provide a practical introduction to the complex and growing field of targeted therapy in hematological malignancies.

Antineoplastic Agents↗
PubMed2003

Development of Varicella-Zoster virus infection in patients with chronic myelogenous leukemia treated with imatinib mesylate.

PURPOSE: Infection with Varicella-Zoster virus (VZV) is an exceptionally rare complication of chronic myelogenous leukemia (CML) without stem cell transplantation. We report 16 patients with CML who developed VZV infection during imatinib mesylate therapy. PATIENTS AND METHODS: From July 1998 until February 2002, 771 patients were included in 11 imatinib mesylate studies for all CML phases in the Departments of Leukemia and Bioimmunotherapy at The University of Texas M. D. Anderson Cancer Center. Sixteen patients developed VZV infection. Charts and follow-up information of were reviewed and analyzed. RESULTS: Sixteen patients (2%) developed a VZV infection [15 episodes of herpes zoster (HZ), 1 varicella]. The baseline characteristics of the 16 patients with infection do not differ significantly from those who did not develop VZV infection, except for time from diagnosis of CML to imatinib (median: 55 versus 25 months, P = 0.0056) and the number of prior therapies (3 versus 1, P < 0.001). All patients received therapy with antiviral agents with good response. Six patients developed postherpetic neuralgia. CONCLUSIONS: Our results suggest that imatinib therapy in CML is associated with low incidence of HZ infection. VZV infection is more frequent with longer duration of CML disease and with prior therapy, does not disseminate, responds well to therapy, and does not mandate a recommendation for HZ prophylaxis in such patients.

Adolescent↗
PubMed2002

Efficacy of the farnesyl transferase inhibitor R115777 in chronic myeloid leukemia and other hematologic malignancies.

We investigated the clinical activity of the farnesyl transferase inhibitor R115777 in 22 patients with chronic myelogenous leukemia (CML) in chronic, accelerated, or blastic phase and in 8 patients with myelofibrosis (MF) and 10 patients with multiple myeloma (MM). R115777 was administered at 600 mg orally twice daily for 4 weeks every 6 weeks. Seven patients with CML (6 in chronic phase, 1 in advanced phase) achieved complete or partial hematologic response. Four of them had a minor cytogenetic response. Responses were transient, with a median duration of 9 weeks (range, 3-23 weeks). Two patients discontinued therapy because of toxicity while in complete hematologic response. Two MF patients had a significant decrease in splenomegaly, one had normalization of white blood cell count and differential, and one became transfusion independent. One patient with MM had a reduction in monoclonal protein of 34%. Adverse events included nausea in 22 patients (55%; all grade 2 or lower) and fatigue in 19 (48%; grade 3 or higher in 1). Other grade 3 or 4 toxicities included skin rash (4 patients, 10%), peripheral neuropathy (2 patients, 5%), and liver toxicity (2 patients, 5%). Patients who responded to therapy had significantly higher plasma vascular endothelial growth factor (VEGF) concentrations prior to treatment than nonresponders. Plasma concentrations decreased significantly during therapy among responders. R115777 showed clinical activity in patients with CML and MF. The effect on VEGF needs to be further investigated to determine whether this might be a possible mechanism of action of R115777.

Adult↗
PubMed2002

Dose escalation of imatinib mesylate can overcome resistance to standard-dose therapy in patients with chronic myelogenous leukemia.

We investigated whether increasing the dose of imatinib mesylate might overcome drug resistance in patients with Philadelphia chromosome-positive (Ph(+)) chronic myelogenous leukemia (CML) whose disease manifests relapse or refractoriness to therapy. Fifty-four patients with Ph(+) CML in chronic phase and with hematologic or cytogenetic resistance or relapse on imatinib mesylate therapy at 400 mg orally daily were treated with a higher dose of 400 mg orally twice daily (800 mg daily, 47 patients; or 600 mg daily increased from 300 mg daily, 7 patients). Among 20 patients treated for hematologic resistance or relapse, 13 (65%) achieved a complete (n = 9) or partial (n = 4) hematologic response, but only 1 had a cytogenetic partial response (Ph reduction from 100% to 10%) and 1 had a minor response (Ph reduction from 100% to 50%). Among 34 patients treated for cytogenetic resistance or relapse, 19 (56%) achieved a complete (n = 6) or partial (n = 7) cytogenetic response. We conclude that higher doses of imatinib mesylate may overcome disease-poor response to conventional doses and that this approach deserves further evaluation as frontline therapy for newly diagnosed CML.

Adult↗
PubMed2002

Imatinib mesylate therapy for relapse after allogeneic stem cell transplantation for chronic myelogenous leukemia.

Twenty-eight adults with chronic myelogenous leukemia (CML) that had relapsed after allogeneic stem cell transplantation (SCT) received imatinib mesylate (400-1000 mg/d). Disease was in chronic phase in 5 patients, accelerated in 15, and blastic in 8 (7 medullary, 1 extramedullary); median time from transplantation to relapse was 9 months (range, 1-137 months). Thirteen patients had undergone salvage donor lymphocyte infusion (DLI) (median time from DLI to imatinib mesylate therapy, 4 months [range, 2-39 months]). The overall response rate was 79% (22 of 28 patients); the complete hematologic response (CHR) rate was 74% (17 of 23 patients), and the cytogenetic response rate was 58% (15 of 26 patients; complete response in 9 [35%] patients). CHR rates were 100% for chronic phase, 83% for accelerated phase, and 43% for blastic phase. The patient with extramedullary blastic disease achieved complete response. Cytogenetic response rates were 63% (12 of 19 patients) for chronic or accelerated phases (complete cytogenetic response in 8) and 43% for blastic phase (3 of 7 patients). At median follow-up of 15 months, 19 patients were alive, 9 with no evidence of disease. The 1-year estimated survival rate was 74%. Five patients had recurrence of grade 3 (3 patients) or grades 1 to 2 (2 patients) graft-versus-host disease (GVHD). Severe granulocytopenia developed in 43% of patients and thrombocytopenia in 27%; both conditions reversed with dose adjustments of imatinib mesylate. We conclude that imatinib mesylate effectively controlled CML that recurred after allogeneic SCT, but it was associated with side effects including myelosuppression and recurrence of severe GVHD.

Administration, Oral↗
PubMed2002

Imatinib mesylate therapy in newly diagnosed patients with Philadelphia chromosome-positive chronic myelogenous leukemia: high incidence of early complete and major cytogenetic responses.

Fifty patients with Philadelphia chromosome-positive (Ph(+)) chronic myelogenous leukemia (CML) in early chronic phase received imatinib mesylate, 400 mg orally daily. After a median follow-up of 9 months, 49 patients (98%) achieved a complete hematologic response and 45 patients (90%) achieved a major cytogenetic response, complete in 36 patients (72%). Compared with similar patients who received interferon-alpha with or without hydroxyurea or other interferon-alpha combination regimens, those receiving imatinib mesylate had higher incidences of complete and major (Ph < 35%) cytogenetic responses at 3 months (34% and 74% versus 1%-4% and 9%-24%, respectively), 6 months (52% and 80% versus 3%-7% and 11%-28%, respectively), and 9 months (60% and 77% versus 5%-11% and 14%-30%, respectively; P <.001). Competitive quantitative polymerase chain reaction (QPCR) studies at 9 months showed a median QPCR value (ratio of BCR-ABL/ABL transcripts x 100) of 0.59% overall and of 0.24% (range, 0.001%-29.5%) for complete cytogenetic response.

Adolescent↗
PubMed2002

Severe periorbital edema secondary to STI571 (Gleevec).

STI571 (imatinib mesylate; Gleevec) is a selective inhibitor of the bcr-abl, c-kit, and platelet-derived growth factor receptor tyrosine kinases. Mild periorbital edema has been noted as a common side effect in Phase I and II trials of this drug for the treatment of patients with chronic myelogenous leukemia and gastrointestinal stromal tumors. The authors report the case of male patient age 63 years who developed severe periorbital edema after treatment with STI571 for chronic myelogenous leukemia. His edema was severe enough to cause visual obstruction due to lower eyelid festoons that ultimately required surgical debulking. Histopathologic analysis of specimens of the excised upper and lower eyelid tissue revealed dermal dendrocytes that expressed the platelet-derived growth factor receptor and c-kit tyrosine kinases, suggesting a possible role for dermal dendrocytes in the development of this toxic effect.

Benzamides↗