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M Talpaz

Publications and source records attributed to M Talpaz.

At least 19 recordsLinked to original sources
PubMed2006

Frequency and clinical significance of BCR-ABL mutations in patients with chronic myeloid leukemia treated with imatinib mesylate.

Mutations of the BCR-ABL kinase domain are a common mechanism of resistance to imatinib in chronic myeloid leukemia. We screened for mutations 171 patients failing imatinib therapy. Sixty-six mutations in 23 amino acids were identified in 62 (36%) patients not responding to imatinib. Phosphate-binding loop (P-loop) mutations were the most frequent (n=24; 36%). By multivariate analysis, factors associated with development of mutations were older age (P=0.026) prior interferon therapy (P=0.026), and accelerated phase or blast phase at time of imatinib failure (P=0.001). After a median follow-up of 38 months (range, 4-68 months) from the start of imatinib therapy, seven patients with non-P-loop and two with P-loop mutation died. By multivariate analysis, development of clonal evolution and higher percentage of peripheral blood basophils were associated with worse survival from the time of imatinib failure. Mutation status had no impact on survival. When survival was measured from the time therapy started, non-P-loop mutations together with duration of response and transformation at the time of failure to imatinib were associated with shorter survival. In conclusion, P-loop mutations were not associated with poor outcome, suggesting that the prognosis of patients who fail imatinib is multifactorial.

Adult↗
PubMed2005

Atiprimod blocks STAT3 phosphorylation and induces apoptosis in multiple myeloma cells.

Multiple myeloma (MM) accounts for 1 % of all cancer deaths. Although treated aggressively, almost all myelomas eventually recur and become resistant to treatment. Atiprimod (2-(3-Diethylaminopropyl)-8,8-dipropyl-2-azaspiro[4,5] decane dimaleate) has exerted anti-inflammatory activities and inhibited oeteoclast-induced bone resorption in animal models and been well tolerated in patients with rheumatoid arthritis in phase I clinical trials. Therefore, we investigated its activity in MM cells and its mechanism of action. We found that Atiprimod inhibited proliferation of the myeloma cell lines U266-B1, OCI-MY5, MM-1, and MM-1R in a time- and dose-dependent manner. Atiprimod blocked U266-B1 myeloma cells in the G(0)/G(1) phase, preventing cell cycle progression. Furthermore, Atiprimod inhibited signal transducer and activator of transcription (STAT) 3 activation, blocking the signalling pathway of interleukin-6, which contributes to myeloma cell proliferation and survival, and downregulated the antiapoptotic proteins Bcl-2, Bcl-X(L), and Mcl-1. Incubation of U266-B1 myeloma cells with Atiprimod induced apoptosis through the activation of caspase 3 and subsequent cleavage of the DNA repair enzyme poly(adenosine diphosphate-ribose) polymerase. Finally, Atiprimod suppressed myeloma colony-forming cell proliferation in fresh marrow cells from five patients with newly diagnosed MM in a dose-dependent fashion. These data suggest that Atiprimod has a role in future therapies for MM.

Apoptosis↗
PubMed2005

Imatinib mesylate suppresses cytokine synthesis by activated CD4 T cells of patients with chronic myelogenous leukemia.

Although imatinib mesylate (IM) is highly effective at inducing complete cytogenetic remission in patients with chronic myelogenous leukemia (CML), it is known to suppress T-cell proliferation in vitro. As cytokines are required for T-cell proliferation, we investigated the effects of IM on cytokine synthesis by T cells of CML patients by assessing cytokine synthesis by activated CD4+ and CD8+ T cells in vitro. The activation of T cells in the whole blood of IM-treated patients (CML-IM) with Staphylococcus enterotoxin B resulted in significantly lower percentages of CD4+ T cells that synthesized interleukin 2 (P = 0.017), interferon-gamma (P = 0.010), and tumor necrosis factor-alpha (P = 0.009) than did the activated T cells of control subjects. The addition of exogenous IM to the cultures of peripheral blood mononuclear cells of CML-IM patients reduced Th1 cytokine synthesis by the CD4+ T cells. Furthermore, IM therapy at clinical doses suppressed the tyrosine phosphorylation of ZAP70. These findings suggest that inhibition of ZAP70 signaling pathway and suppression of Th1 cytokine synthesis by CD4+ T cells required the presence of IM at the time of T-cell activation through the T-cell receptor.

Antineoplastic Agents↗
PubMed2002

Comparison of competitive-nested PCR and real-time PCR in detecting BCR-ABL fusion transcripts in chronic myeloid leukemia patients.

Real-time RT-PCR has great advantages for estimating transcript levels in a variety of situations. These include relative rapid assay times (hours), reliability and ease of performing replicate analyses. In contrast, competitive PCR is a very labor-intensive procedure requiring a few days to generate useful data. We compared the same samples from CML patients by both methods. Importantly, we used the Bcr-Abl junction plasmid DNA, which is used as a competitor in the manual competitive PCR assay, to generate a standard curve for the real-time assay. This permitted reporting the real-time data as the number of BCR-ABL transcripts per microg of total RNA, which is the same format used for the competitive PCR assay. In this study, a total of 435 peripheral blood and marrow samples from 285 CML patients were analyzed by RT-PCR; these patients were undergoing therapy by STI-571, interferon, and bone marrow transplantation treatment. Most samples also had assay values for the Philadelphia chromosome (Ph), FISH and Western blotting for the Bcr-Abl oncoprotein. Our findings indicated that the real-time assay was less sensitive than the manual competitive RT-PCR assay (t = 5.118; P < 0.001). Of interest, the transcript levels in cell line mixtures with various ratios of K562/KG-1 (BCR-ABL positive/negative) cells were also significantly higher with the competitive RT-PCR assays than real-time RT-PCR, except for levels of BCR-ABL below 200 transcripts per microg of RNA. In both patient and cell line experiments, dividing the BCR-ABL transcripts by the total ABL transcripts virtually eliminated the difference between real-time BCR-ABL transcript values and quantitative competitive BCR-ABL transcript values, indicating that both BCR-ABL and ABL transcripts were underestimated by the real-time assay. In addition, the increased sensitivity of the nested, competitive RT-PCR was readily apparent in patients with minimal residual disease, which by the real-time were negative in the majority of patients but were positive by nested, competitive RT-PCR in 44.6% (n = 29) of samples analyzed (n = 65). These findings indicate that real-time RT-PCR, when normalized for the total ABL transcripts, can be used to monitor CML patients during therapy, but we suggest that nested, competitive RT-PCR be used to determine BCR-ABL/ABL transcript ratios at low transcript values or especially when real-time analyses are negative.

Fusion Proteins, bcr-abl↗
PubMed2002

Quantitative measurement of BCR/abl transcripts using real-time polymerase chain reaction.

BACKGROUND: Quantitative real-time polymerase chain reaction (Q-Rt-PCR) is a new tool in the detection and quantification of the BCR/abl fusion transcripts in chronic myelogenous leukemia (CML). This study investigates its specificity, sensitivity and potential clinical usefulness. PATIENTS AND METHODS: Parallel analysis of Q-Rt-PCR and the conventional reverse transcription-mediated PCR (RT-PCR) were performed on 567 samples from 481 patients. Treatment response was monitored by Q-Rt-PCR at 6 and 12 months of 61 patients on STI-571 and 103 patients on interferon. RESULTS: The concordance rate between Q-Rt-PCR and RT-PCR was 96.3% (546/567), with 341 positives and 205 negatives. The positive equivalents ranged from 2 x 10(-6) to 1.2 microg of K562 cell RNA. Karyotyping in 372 samples revealed excellent correlation with Q-Rt-PCR measurements (P < 0.001). Setting residual BCR/abl < 0.01 as an early goal of molecular response, we observed that STI-571 induced a better response than interferon: 49% (20 of 41 patients) versus 35% (15 of 62 patients) at 6 months (P = 0.025) and 52% (32 of 61 patients) versus 34% (35 of 103 patients) at 12 months (P = 0.01), respectively. CONCLUSIONS: Q-Rt-PCR provides reliable measurements of BCR/abl fusion transcripts. It is potentially useful in assessing molecular residual disease after therapy.

Base Sequence↗
PubMed2001

Response to therapy is independently associated with survival prolongation in chronic myelogenous leukemia in the blastic phase.

BACKGROUND: Achievement of minimal tumor burden, such as complete response, has been accepted as a surrogate marker for improved survival in many solid and hematologic carcinomas. Several new agents have been approved recently for orphan disease indications or unmet medical needs, based on response analyses. This has not been the case for chronic myelogenous leukemia in the blastic phase (CML-BP), despite its poor prognosis, because response has not been proven to be a valuable endpoint for survival prolongation. The purpose of this study was to analyze the effect of response in CML-BP on survival prolongation. STUDY GROUP AND METHODS In total, 328 patients with CML-BP referred from 1989 to 1999 were studied; 311 patients received therapy for CML-BP, and 275 were evaluable for response. Blastic phase CML was defined by the presence of 30% or more blasts in the blood or bone marrow, or extramedullary disease. Treatment responses were reviewed and categorized as proposed in previous large studies. Four categoric response groups were defined further based on significant differences in outcome: cytogenetic response, hematologic response, bone marrow improvement, and failure. The association of treatment response with survival was evaluated by multivariate and landmark analyses. RESULTS: The association of response with survival was analyzed among the 275 patients who had evaluable responses, and follow-up information was documented. Univariate analysis of pretreatment characteristics found performance status, hemoglobin levels, platelet counts, peripheral blasts, additional chromosomal abnormalities, and blastic phase morphology as showing significant associations with survival (P < 0.1). A multivariate analysis found platelet counts and blastic morphology as independent significant factors associated with survival (P < 0.05). A landmark analysis conducted at 8 weeks from start of therapy showed the beneficial effect of achieving response on survival prolongation (P < 0.001). A repeat multivariate at the 8-week landmark time in the 240 patients alive at that time, which included pretreatment characteristics and treatment response, confirmed the independent significant association of morphology (P = 0.003), platelet counts (P = 0.04), and response (P < 0.001) with survival. CONCLUSIONS: Response to therapy is a significant independent factor associated with survival prolongation and maybe an acceptable therapeutic endpoint for approving new treatments in CML-BP.

Adolescent↗
PubMed2001

Pilot study of low-dose interleukin-11 in patients with bone marrow failure.

PURPOSE: Interleukin-11 (IL-11) is a thrombopoietic cytokine that attenuates postchemotherapy thrombocytopenia at doses of 50 microg/kg/d subcutaneously. Very little is known about the activity of IL-11 in patients with bone marrow failure states. PATIENTS AND METHODS: Our preliminary experience with IL-11 at doses of 50 microg/kg/d suggested that patients with bone marrow failure developed significant peripheral and pulmonary edema after the prolonged dosing necessary for treating these conditions. We, therefore, initiated a study of low-dose IL-11 (starting dose, 10 microg/kg/d). RESULTS: Sixteen patients were assessable for response. Six patients had diploid cytogenetics; the others had a variety of chromosomal abnormalities. Six (38%) of 16 patients showed a platelet response to IL-11, and two had a multilineage response (to IL-11 alone, n = 1; to IL-11 plus G-CSF and erythropoietin, n = 1). The median increase in peak platelet counts was 95 x 10(9)/L above baseline in the responders (range, increase of 55 x 10(9)/L to 130 x 10(9)/L above baseline). Responders included five of 11 patients with myelodysplasia and one of four patients with aplastic anemia. Response durations were 12, 13, 14+, 25, 30, and 30+ weeks. Side effects of IL-11 were mild (peripheral edema, n = 7; conjunctival injection, n = 7; myalgia, n = 1; all grade 1). Seven patients had no side effects. CONCLUSION: Our pilot study suggests that administration of low-dose IL-11 (10 microg/kg/d) can raise platelet counts without significant toxicity in selected thrombocytopenic patients with bone marrow failure.

Adolescent↗
PubMed2001

Homoharringtonine: history, current research, and future direction.

BACKGROUND: Cephalotoxine esters, including homoharringtonine (HHT), have shown encouraging activity in leukemia in initial studies in China and in later studies in the U.S. METHODS: The authors conducted a review of the literature to examine the studies pertinent to HHT in relation to preclinical studies and Phase I-II trials in patients with hematologic malignancies and solid tumors. RESULTS: HHT and analogues appear to induce differentiation and apoptosis. Studies from China reported high response rates in patients with leukemia. Trials in the U.S. using short HHT infusions (3-4 mg/m(2) daily for 5 days) resulted in a high incidence of cardiovascular complications that were reduced using continuous infusion schedules of 3-7 mg/m(2) daily for 5-7 days initially, and later lower dose schedules of 2.5 mg/m(2) daily for 7-14 days. Results in solid tumors were negative. However encouraging results were reported in patients with acute myeloid leukemia, myelodysplastic syndrome, acute promyelocytic leukemia, and, most important, chronic myeloid leukemia (CML). In CML patients, HHT has been investigated alone and in combination with interferon-alpha and low-dose cytarabine in late and early chronic phases, with positive results. Additional areas of interest include the potential use of HHT for the treatment of central nervous system leukemia, polycythemia vera, and other nonmalignant conditions such as malaria. New semisynthetic preparations and HHT derivatives that bypass multidrug resistance may improve the efficacy and toxicity profiles, and broaden the range of antitumor efficacy. CONCLUSIONS: HHT and its derivatives appear to have promising activity in hematologic malignancies, a finding that needs to be pursued.

Antineoplastic Agents, Phytogenic↗
PubMed2001

Phase 1 study of polyethylene glycol formulation of interferon alpha-2B (Schering 54031) in Philadelphia chromosome-positive chronic myelogenous leukemia.

Interferon alpha (IFN-alpha) therapy improves prognosis in Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia (CML). Polyethylene glycol (PEG) attached to IFN-alpha prolongs its half-life and may offer better therapy. The aims of this phase 1 study were to define the maximal tolerated dose (MTD), dose-limiting toxicities (DLTs), and response with PEG IFN-alpha-2b. Twenty-seven adults with Ph(+) CML in chronic or accelerated phases, in whom IFN-alpha treatment had failed, were studied. Patients had hematologic (9 patients) or cytogenetic resistance (12 patients) or intolerance to IFN-alpha (6 patients). PEG IFN-alpha-2b was given as a weekly subcutaneous injection starting at 0.75 microg/kg weekly and escalating to 1.5, 3, 4.5, 6, 7.5, and 9.0 microg/kg. The MTD was defined at 7.5 to 9 microg/kg; DLT included severe fatigue, neurotoxicity, liver function abnormalities, and myelosuppression. Longer administration of PEG IFN-alpha-2b resulted in chronic side effects not observed earlier, which defined the MTD and DLT. The proposed phase 2 dose of PEG IFN-alpha-2b was 6 microg/kg weekly. Among 19 patients with active disease, 7 (37%) achieved complete hematologic response (CHR); 2 (11%) had a cytogenetic response (complete). Among 8 patients treated in CHR, 7 (87%) improved cytogenetic response to complete (4 patients) or partial (3 patients). All 6 patients intolerant to IFN-alpha tolerated PEG IFN-alpha-2b; 4 improved their cytogenetic response. The results show that PEG IFN-alpha-2b is easier to deliver (once weekly), better tolerated, and perhaps more effective than IFN-alpha.

Adult↗
PubMed2001

Chronic myelogenous leukemia blast cell proliferation is inhibited by peptides that disrupt Grb2-SoS complexes.

Chronic myelogenous leukemia (CML) is commonly characterized by the presence of the p210(Bcr-Abl) oncoprotein. Many downstream effectors of Bcr-Abl have been described, including activation of the Grb2-SoS-Ras-MAP kinase (Erk) pathway. The precise contributions of these signal-transduction proteins in CML blast cells in human patients are not yet well defined. To gain further insight into the importance of Grb2 for CML, peptides that disrupt Grb2-SoS complexes were tested. These high-affinity Grb2-binding peptides (HAGBPs) can autonomously shuttle into cells and function by binding to the N-terminal SH3 domain of Grb2. The HAGBPs were analyzed for their effects on Bcr-Abl-expressing cell lines and freshly isolated CML blast cells from patients. They induced a dramatic decrease in the proliferation of CML cell lines. This was not observed with point-mutated control peptides with abolished Grb2SH3(N) binding. As expected, Grb2-SoS complexes were greatly diminished in the HAGBP-treated cells, and MAP kinase activity was significantly reduced as determined by an activation-specific phospho-MAPK antibody. Furthermore, cell fractions that are enriched for blast cells from CML patients with active disease were also incubated with the Grb2 blocker peptides. The HAGBPs led to a significant proliferation reduction of these cells in the majority of the isolates, but not in all patients' cells. These results show that, in addition to the direct targeting of Bcr-Abl, selective inhibition of Grb2 protein complexes may be a therapeutic option for a significant number of CML patients.

3T3 Cells↗
PubMed2001

Expression of apoptosis proteins in chronic myelogenous leukemia: associations and significance.

BACKGROUND: The mechanisms favoring the growth advantage of Philadelphia chromosome positive cells over normal cells in chronic myelogenous leukemia (CML) are not fully elucidated but could be due partly to altered apoptosis and longer survival of CML clones. Also, little is known about the biologic characteristics of disease progression in CML. Bcl-2 expression has been demonstrated to exert an antiapoptotic effect resulting in increased cell survival. Other proteins such as Bax and Bad are proapoptotic proteins. Fas, a cell surface protein, can be triggered by an appropriate death-promoting ligand (FasL) to activate downstream caspases pivotal in initiation of programmed cell death. Although the mechanisms underlying cellular proliferative and apoptotic pathways are complex, with involvement of multiple interlocking proteins, the relative expression of pro- and antiapoptotic proteins may have an influence on disease progression. This study aimed to determine whether the changes in the cellular expression of Bcl-2, Bax, and Fas correlate with caspase-3 activity and disease progression in CML, or with response to interferon (IFN)-alpha therapy and prognosis in early chronic phase CML. METHODS: Bcl-2, Bax, and Fas expression were measured on whole cell lysates from bone marrow mononuclear cell fractions by Western blot analysis and quantitative radioimmunoassay. Caspase-3 activity was determined using the DEVD system. Specimens from 203 patients with CML were examined. These included 130 patients in early chronic phase disease (ECP; diagnosis to therapy, < or =12 months), 33 patients in late chronic phase (diagnosis to therapy, > 12 months), 27 patients in accelerated phase, and 13 patients in blastic phase. Correlations between apoptosis proteins and CML phases, risk groups in ECP, and response to IFN-alpha therapy and survival in ECP were investigated by standard statistical methods, and positive findings were assessed by multivariate analysis. RESULTS: Levels of Bcl-2, Fas, Bax, and caspase-3 activity did not correlate with disease progression. Among patients in ECP, higher Fas levels correlated with poorer risk groups (P = 0.05) and higher caspase-3 activity correlated with better risk groups (P = 0.048). With IFN-alpha therapy, major cytogenetic responses were noted in 30% of patients with high Fas and 53% with low Fas (P = 0.016) and failure to achieve a complete hematologic response (CHR) in 25% versus 2% (P = 0.0001). Survival was shorter with high Fas levels (5-year rates, 71% vs. 52%; P = 0.002), and the independent poor prognostic significance of high Fas levels was confirmed by multivariate analysis (P = 0.014). Response to IFN-alpha therapy and survival were not significantly different by different levels of Bcl-2, Bax, or caspase-3 activity. CONCLUSIONS: High Fas levels were associated with intrinsically worse disease at diagnosis, whereas high caspase-3 activity was associated with good risk disease. In ECP CML, high Fas levels were associated with significantly worse response to IFN-alpha therapy and with significantly worse survival. The influence of these cellular proteins and caspase-3 activity on apoptosis in CML is complex and merits further investigation.

Adolescent↗
PubMed2001

BCR rearrangement-negative chronic myelogenous leukemia revisited.

PURPOSE: To document the characteristics of patients with major breakpoint cluster region (M-bcr) rearrangement-negative chronic myelogenous leukemia (CML). PATIENTS AND METHODS: The hematopathologist, who was blinded to patients' molecular status, reviewed the referral bone marrows and peripheral-blood smears from 26 patients with Philadelphia (Ph) translocation-negative CML who lacked Bcr rearrangement (and other evidence of a Bcr-Abl anomaly) and 14 patients (controls) with chronic-phase Ph-positive CML. Clinical data was ascertained by chart review. RESULTS: Among the 26 M-bcr rearrangement-negative CML patients, three pathologic subtypes emerged: (1) patients indistinguishable from classic CML (n = 9), (2) patients with atypical CML (n = 8), and (3) patients with chronic neutrophilic leukemia (n = 9). Among the 14 patients with Ph-positive CML who were included in the blinded review, 13 were classified as classic CML, and one was classified as atypical CML. The only statistically significant difference between M-bcr rearrangement-negative subgroups was in the proportion of patients having karyotypic abnormalities, an observation common only in patients with atypical CML (P = 0.008). However, the small number of patients in each subgroup limited our ability to differentiate between them. Interferon alfa induced complete hematologic remission in five of 14 patients; four of these remissions lasted more than 5 years. Only one of 26 patients developed blast crisis. The median survival of the 26 patients was 37 months. CONCLUSION: Patients with M-bcr rearrangement-negative CML fall into three morphologic subgroups. Disease evolution does not generally involve blastic transformation. Instead, patients show progressive organomegaly, leukocytosis, anemia, and thrombocytosis. Some patients in each subgroup can respond to interferon alfa.

Adult↗
PubMed2001

Autocrine cell suicide in a Burkitt lymphoma cell line (Daudi) induced by interferon alpha: involvement of tumor necrosis factor as ligand for the CD95 receptor.

The CD95 receptor, a member of the tumor necrosis factor (TNF) receptor superfamily, mediates signals for cell death on specific ligand or antibody engagement. It was hypothesized that interferon alpha (IFN-alpha) induces apoptosis through activation of the CD95-mediated pathway and that CD95 and ligands of the death domain may belong to the group of IFN-stimulated genes. Therefore, the effect of IFN-alpha on CD95-CD95L expression, on the release of TNF-alpha, and on TNF receptor 1 expression in an IFN-sensitive human Burkitt lymphoma cell line (Daudi) was investigated. After 5 days' incubation, apoptosis in 81% of IFN-alpha-treated Daudi cells was preceded by a release of TNF-alpha and an induction of CD95 receptor expression. Although supernatants of IFN-treated Daudi cells induced apoptosis of CD95-sensitive Jurkat cells, CD95L was undetectable on protein or on messenger RNA levels, and the weak initial expression of TNF receptor 1 increased only slightly during IFN treatment. Surprisingly, binding of TNF-alpha to CD95 was observed and confirmed by 3 different techniques-enzyme-linked immunosorbent assay using immobilized CD95:Fc-immunoglobulin G, immunoprecipitation assay using CD95 receptor precipitates of Daudi cells, and binding of sodium iodide 125-TNF-alpha to Daudi cells, which was strongly stimulated by IFN-alpha and inhibited by CD95L, CD95:Fc, unlabeled TNF-alpha, and anti-TNF-alpha antibody. Preincubation of Daudi cells with antagonists of the CD95-mediated pathway resulted in an inhibition of IFN-alpha-mediated cell death. The present investigation shows that IFN-alpha induces autocrine cell suicide of Daudi cells by a cross-talk between the CD95 receptor and TNF-alpha. The CD95 receptor can be considered a third TNF receptor, in addition to p55 and p75.

Antineoplastic Agents↗
PubMed2001

Down-regulation of interleukin-3/granulocyte-macrophage colony-stimulating factor receptor beta-chain in BCR-ABL(+) human leukemic cells: association with loss of cytokine-mediated Stat-5 activation and protection from apoptosis after BCR-ABL inhibition.

Several signaling cascades are engaged by expression of the p210 bcr-abl tyrosine kinase, and evidence suggests that these signals drive leukemogenesis. In this report, signaling pathways were examined and compared between cells derived from leukemic patients and cells expressing a bcr-abl construct (MBA). The effects of acute inhibition of bcr-abl with STI-571 on these signals and the survival of bcr-abl-expressing cells were also evaluated. Expression of bcr-abl in interleukin-3 (IL-3)/granulocyte-macrophage colony-stimulating factor (GM-CSF)-dependent Mo7e cells (MBA) resulted in growth factor independence, constitutive activation of Stat-5 phosphorylation, engagement of mitogen-activated protein (MAP) kinase signals, and increased expression of PTP1B and bcl-x(L). STI-571 inhibited cell growth and induced apoptosis in bcr-abl-expressing cells (MBA, K562, BV-173, KBM5) but not in bcr-abl(-) tumor cells (Mo7e, KG-1, ME-180, Daudi). STI-571-mediated apoptosis correlated with the inhibition of Stat-5 and MAP kinase activation and a reduction in overexpressed bcl-x(L) but not in PTP1B. Inhibitor had no effect on IL-3/GM-CSF-dependent Mo7e cell signaling and did not prevent activation of the other Jak/Stat pathways (interferon alpha, IL-3/GM-CSF). However, neither IL-3 nor GM-CSF could reactivate Stat-5 after the STI-571-mediated inhibition of bcr-abl. Expression of the common beta-chain of the IL-3/GM-CSF receptor was down-regulated in Stat-5-activated myeloid leukemic cells, suppressing IL-3/GM-CSF signal transduction and the ability of these cytokines to provide apoptotic protection. These studies suggest that bcr-abl activates cytokine-independent mechanisms of survival while inactivating intrinsic cytokine signaling cascades, making bcr-abl(+) myeloid cells vulnerable to apoptosis after bcr-abl inactivation.

Apoptosis↗
PubMed2001

Efficacy and safety of a specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia.

BACKGROUND: BCR-ABL is a constitutively activated tyrosine kinase that causes chronic myeloid leukemia (CML). Since tyrosine kinase activity is essential to the transforming function of BCR-ABL, an inhibitor of the kinase could be an effective treatment for CML. METHODS: We conducted a phase 1, dose-escalating trial of STI571 (formerly known as CGP 57148B), a specific inhibitor of the BCR-ABL tyrosine kinase. STI571 was administered orally to 83 patients with CML in the chronic phase in whom treatment with interferon alfa had failed. Patients were successively assigned to 1 of 14 doses ranging from 25 to 1000 mg per day. RESULTS: Adverse effects of STI571 were minimal; the most common were nausea, myalgias, edema, and diarrhea. A maximal tolerated dose was not identified. Complete hematologic responses were observed in 53 of 54 patients treated with daily doses of 300 mg or more and typically occurred in the first four weeks of therapy. Of the 54 patients treated with doses of 300 mg or more, cytogenetic responses occurred in 29, including 17 (31 percent of the 54 patients who received this dose) with major responses (0 to 35 percent of cells in metaphase positive for the Philadelphia chromosome); 7 of these patients had complete cytogenetic remissions. CONCLUSIONS: STI571 is well tolerated and has significant antileukemic activity in patients with CML in whom treatment with interferon alfa had failed. Our results provide evidence of the essential role of BCR-ABL tyrosine kinase activity in CML and demonstrate the potential for the development of anticancer drugs based on the specific molecular abnormality present in a human cancer.

Adult↗
PubMed2001

Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome.

BACKGROUND: BCR-ABL, a constitutively activated tyrosine kinase, is the product of the Philadelphia chromosome. This enzyme is present in virtually all cases of chronic myeloid leukemia (CML) throughout the course of the disease, and in 20 percent of cases of acute lymphoblastic leukemia (ALL). On the basis of the substantial activity of the inhibitor in patients in the chronic phase, we evaluated STI571 (formerly known as CGP 57148B), a specific inhibitor of the BCR-ABL tyrosine kinase, in patients who had CML in blast crisis and in patients with ALL who had the Ph chromosome. METHODS: In this dose-escalating pilot study, 58 patients were treated with STI571; 38 patients had a myeloid blast crisis and 20 had ALL or a lymphoid blast crisis. Treatment was given orally at daily doses ranging from 300 to 1000 mg. RESULTS: Responses occurred in 21 of 38 patients (55 percent) with a myeloid-blast-crisis phenotype; 4 of these 21 patients had a complete hematologic response. Of 20 patients with a lymphoid blast crisis or ALL, 14 (70 percent) had a response, including 4 who had complete responses. Seven patients with a myeloid blast crisis continue to receive treatment and remain in remission from 101 to 349 days after starting the treatment. All but one patient with a lymphoid blast crisis or ALL has relapsed. The most frequent adverse effects were nausea, vomiting, edema, thrombocytopenia, and neutropenia. CONCLUSIONS: The BCR-ABL tyrosine kinase inhibitor STI571 is well tolerated and has substantial activity in the blast crises of CML and in Ph-positive ALL.

Adult↗