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Daryl Sonnichsen,
David J Dorer,
Jorge Cortes,
Moshe Talpaz,
Michael W Deininger, Neil P Shah,
Hagop M Kantarjian,
Dale Bixby,
Michael J Mauro,
Ian W Flinn,
Jeffrey Litwin,
Christopher D Turner,
Frank G Haluska
[show abstract]
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ABSTRACT: PURPOSE: Cardiac dysfunction, particularly QT interval prolongation, has been observed with tyrosine kinase inhibitors approved to treat chronic myeloid leukemia. This study examines the effects of ponatinib on cardiac repolarization in patients with refractory hematological malignancies enrolled in a phase 1 trial. METHODS: Electrocardiograms (ECGs) were collected at 3 dose levels (30, 45, and 60 mg) at 6 time points. Electrocardiographic parameters, including QTc interval, were measured, and 11 morphological analyses were conducted. Central tendency analyses of ECG parameters were performed using time-point and time-averaged approaches. All patients with at least 2 baseline ECGs and 1 on-treatment ECG were included in the analyses. Patients with paired ECGs and plasma samples were included in the pharmacokinetic/pharmacodynamic analysis to examine the relationship between ponatinib plasma concentration and change from baseline in QT intervals. RESULTS: Thirty-nine patients at the 30-, 45-, and 60-mg dose levels were included in the central tendency and morphological analyses. There was no significant effect on cardiac repolarization, as evidenced by non-clinically significant mean QTcF changes from baseline of -10.9, -3.6, and -5.0 ms for the 30-, 45-, and 60-mg dose levels, respectively. The morphological analysis revealed 2 patients with atrial fibrillation and 2 with T wave inversion. Seventy-five patients were included in the pharmacokinetic/pharmacodynamic analysis across all dose levels. The slope of the relationship for QTcF versus plasma ponatinib concentration was not positive (-0.0171), indicating no exposure-effect relationship. CONCLUSIONS: Ponatinib is associated with a low risk of QTc prolongation in patients with refractory hematological malignancies.
Cancer Chemotherapy and Pharmacology 04/2013; · 2.83 Impact Factor
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Jorge E Cortes,
Hagop Kantarjian, Neil P Shah,
Dale Bixby,
Michael J Mauro,
Ian Flinn,
Thomas O'Hare,
Simin Hu,
Narayana I Narasimhan,
Victor M Rivera,
Tim Clackson,
Christopher D Turner,
Frank G Haluska,
Brian J Druker,
Michael W N Deininger,
Moshe Talpaz
[show abstract]
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ABSTRACT: Resistance to tyrosine kinase inhibitors in patients with chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL) is frequently caused by mutations in the BCR-ABL kinase domain. Ponatinib (AP24534) is a potent oral tyrosine kinase inhibitor that blocks native and mutated BCR-ABL, including the gatekeeper mutant T315I, which is uniformly resistant to tyrosine kinase inhibitors.
In this phase 1 dose-escalation study, we enrolled 81 patients with resistant hematologic cancers, including 60 with CML and 5 with Ph-positive ALL. Ponatinib was administered once daily at doses ranging from 2 to 60 mg. Median follow-up was 56 weeks (range, 2 to 140).
Dose-limiting toxic effects included elevated lipase or amylase levels and pancreatitis. Common adverse events were rash, myelosuppression, and constitutional symptoms. Among Ph-positive patients, 91% had received two or more approved tyrosine kinase inhibitors, and 51% had received all three approved tyrosine kinase inhibitors. Of 43 patients with chronic-phase CML, 98% had a complete hematologic response, 72% had a major cytogenetic response, and 44% had a major molecular response. Of 12 patients who had chronic-phase CML with the T315I mutation, 100% had a complete hematologic response and 92% had a major cytogenetic response. Of 13 patients with chronic-phase CML without detectable mutations, 100% had a complete hematologic response and 62% had a major cytogenetic response. Responses among patients with chronic-phase CML were durable. Of 22 patients with accelerated-phase or blast-phase CML or Ph-positive ALL, 36% had a major hematologic response and 32% had a major cytogenetic response.
Ponatinib was highly active in heavily pretreated patients with Ph-positive leukemias with resistance to tyrosine kinase inhibitors, including patients with the BCR-ABL T315I mutation, other mutations, or no mutations. (Funded by Ariad Pharmaceuticals and others; ClinicalTrials.gov number, NCT00660920.).
New England Journal of Medicine 11/2012; 367(22):2075-88. · 53.30 Impact Factor
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Hagop M Kantarjian, Neil P Shah,
Jorge E Cortes,
Michele Baccarani,
Mohan B Agarwal,
María Soledad Undurraga,
Jianxiang Wang,
Juan Julio Kassack Ipiña,
Dong-Wook Kim,
Michinori Ogura,
Carolina Pavlovsky,
Christian Junghanss,
Jorge H Milone,
Franck E Nicolini,
Tadeusz Robak,
Jan Van Droogenbroeck,
Edo Vellenga,
M Brigid Bradley-Garelik,
Chao Zhu,
Andreas Hochhaus
[show abstract]
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ABSTRACT: Dasatinib is a highly potent BCR-ABL inhibitor with established efficacy and safety in imatinib-resistant/-intolerant patients with chronic myeloid leukemia (CML). In the phase 3 DASISION trial, patients with newly diagnosed chronic-phase (CP) CML were randomized to receive dasatinib 100 mg (n = 259) or imatinib 400 mg (n = 260) once daily. Primary data showed superior efficacy for dasatinib compared with imatinib after 12 months, including significantly higher rates of complete cytogenetic response (CCyR), confirmed CCyR (primary end point), and major molecular response (MMR). Here, 24-month data are presented. Cumulative response rates by 24 months in dasatinib and imatinib arms were: CCyR in 86% versus 82%, MMR in 64% versus 46%, and BCR-ABL reduction to ≤ 0.0032% (4.5-log reduction) in 17% versus 8%. Transformation to accelerated-/ blast-phase CML on study occurred in 2.3% with dasatinib versus 5.0% with imatinib. BCR-ABL mutations, assessed after discontinuation, were detected in 10 patients in each arm. In safety analyses, fluid retention, superficial edema, myalgia, vomiting, and rash were less frequent with dasatinib compared with imatinib, whereas pleural effusion and grade 3/4 thrombocytopenia were more frequent with dasatinib. Overall, dasatinib continues to show faster and deeper responses compared with imatinib, supporting first-line use of dasatinib in patients with newly diagnosed CML-CP. This study was registered at ClinicalTrials.gov: NCT00481247.
Blood 12/2011; 119(5):1123-9. · 9.90 Impact Factor
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Christian Hurtz,
Katerina Hatzi,
Leandro Cerchietti,
Melanie Braig,
Eugene Park,
Yong-mi Kim,
Sebastian Herzog,
Parham Ramezani-Rad,
Hassan Jumaa,
Martin C Müller,
Wolf-Karsten Hofmann,
Andreas Hochhaus,
B Hilda Ye,
Anupriya Agarwal,
Brian J Druker, Neil P Shah,
Ari M Melnick,
Markus Müschen
[show abstract]
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ABSTRACT: Chronic myeloid leukemia (CML) is induced by the oncogenic BCR-ABL1 tyrosine kinase and can be effectively treated for many years with tyrosine kinase inhibitors (TKIs). However, unless CML patients receive life-long TKI treatment, leukemia will eventually recur; this is attributed to the failure of TKI treatment to eradicate leukemia-initiating cells (LICs). Recent work demonstrated that FoxO factors are critical for maintenance of CML-initiating cells; however, the mechanism of FoxO-dependent leukemia initiation remained elusive. Here, we identified the BCL6 protooncogene as a critical effector downstream of FoxO in self-renewal signaling of CML-initiating cells. BCL6 represses Arf and p53 in CML cells and is required for colony formation and initiation of leukemia. Importantly, peptide inhibition of BCL6 in human CML cells compromises colony formation and leukemia initiation in transplant recipients and selectively eradicates CD34(+) CD38(-) LICs in patient-derived CML samples. These findings suggest that pharmacological inhibition of BCL6 may represent a novel strategy to eradicate LICs in CML. Clinical validation of this concept could limit the duration of TKI treatment in CML patients, which is currently life-long, and substantially decrease the risk of blast crisis transformation.
Journal of Experimental Medicine 09/2011; 208(11):2163-74. · 13.85 Impact Factor
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ABSTRACT: Clinical variables associated with ecotropic viral integration site 1 (EVI1) translocations were evaluated in 42 consecutive chronic myeloid leukemia (CML) patients in myeloid blast crisis (MBC). Translocations were confirmed with fluorescence in situ hybridization, and Western blot analysis demonstrated EVI1 expression. Translocations of EVI1 were present in 3 of 24 (12%) patients whose disease evolved MBC before tyrosine kinase inhibitor (TKI) exposure, and 7 of 18 (39%) patients who had received one or more TKIs. Univariate analysis showed that prior TKI therapy was the only clinical variable that was significantly associated with EVI1 translocation (P = 0.047). TKI-resistant BCR-ABL1 mutations were present in 71% of MBC patients with EVI1 translocations at the time of disease progression. These observations suggest that EVI1 overexpression collaborates with BCR-ABL1 in the evolution of TKI-resistant MBC. Inhibition of c-ABL kinase-mediated DNA double-strand repair by TKIs may predispose to EVI1 translocation in this setting.
Cancer Genetics 07/2011; 204(7):392-7.
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Hagop Kantarjian, Neil P Shah,
Andreas Hochhaus,
Jorge Cortes,
Sandip Shah,
Manuel Ayala,
Beatriz Moiraghi,
Zhixiang Shen,
Jiri Mayer,
Ricardo Pasquini,
Hirohisa Nakamae,
Françoise Huguet,
Concepción Boqué,
Charles Chuah,
Eric Bleickardt,
M Brigid Bradley-Garelik,
Chao Zhu,
Ted Szatrowski,
David Shapiro,
Michele Baccarani
[show abstract]
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ABSTRACT: Treatment with dasatinib, a highly potent BCR-ABL kinase inhibitor, has resulted in high rates of complete cytogenetic response and progression-free survival among patients with chronic myeloid leukemia (CML) in the chronic phase, after failure of imatinib treatment. We assessed the efficacy and safety of dasatinib, as compared with imatinib, for the first-line treatment of chronic-phase CML.
In a multinational study, 519 patients with newly diagnosed chronic-phase CML were randomly assigned to receive dasatinib at a dose of 100 mg once daily (259 patients) or imatinib at a dose of 400 mg once daily (260 patients). The primary end point was complete cytogenetic response by 12 months, confirmed on two consecutive assessments at least 28 days apart. Secondary end points, including major molecular response, were tested at a significance level of 0.0001 to adjust for multiple comparisons.
After a minimum follow-up of 12 months, the rate of confirmed complete cytogenetic response was higher with dasatinib than with imatinib (77% vs. 66%, P=0.007), as was the rate of complete cytogenetic response observed on at least one assessment (83% vs. 72%, P=0.001). The rate of major molecular response was higher with dasatinib than with imatinib (46% vs. 28%, P<0.0001), and responses were achieved in a shorter time with dasatinib (P<0.0001). Progression to the accelerated or blastic phase of CML occurred in 5 patients who were receiving dasatinib (1.9%) and in 9 patients who were receiving imatinib (3.5%). The safety profiles of the two treatments were similar.
Dasatinib, administered once daily, as compared with imatinib, administered once daily, induced significantly higher and faster rates of complete cytogenetic response and major molecular response. Since achieving complete cytogenetic response within 12 months has been associated with better long-term, progression-free survival, dasatinib may improve the long-term outcomes among patients with newly diagnosed chronic-phase CML. (ClinicalTrials.gov number, NCT00481247.)
New England Journal of Medicine 06/2010; 362(24):2260-70. · 53.30 Impact Factor
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Michael B Lilly,
Oliver G Ottmann, Neil P Shah,
Richard A Larson,
Josy J Reiffers,
Gerhard Ehninger,
Martin C Müller,
Aude Charbonnier,
Eduardo Bullorsky,
Herve Dombret,
Mary Brigid Bradley-Garelik,
Chao Zhu,
Giovanni Martinelli
[show abstract]
[hide abstract]
ABSTRACT: Dasatinib 70 mg twice daily is indicated for Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) intolerant or resistant to imatinib. In patients with chronic-phase chronic myelogenous leukemia, once-daily dosing has similar efficacy with improved safety, compared with twice-daily dosing. A phase 3 study (n = 611) assessed the efficacy and safety of dasatinib 140 mg once daily versus 70 mg twice-daily in patients with advanced phase chronic myelogenous leukemia or Ph+ ALL resistant or intolerant to imatinib. Here, results from the Ph+ ALL subset (n = 84) with a 2-year follow-up are reported. Patients were randomly assigned to receive dasatinib either 140 mg once daily (n = 40) or 70 mg twice daily (n = 44). The rate of confirmed major hematologic response with once-daily dosing (38%) was similar to that with twice-daily dosing (32%). The rate of major cytogenetic response with once-daily dosing (70%) was higher than that with twice-daily dosing (52%). Compared with the twice-daily schedule, the once-daily schedule had longer progression-free survival (median, 3.0 months versus 4.0 months, respectively) and shorter overall survival (median, 9.1 months versus 6.5 months, respectively). Overall safety profiles were similar between two groups, with nonhematologic adverse events being mostly grade 1 or 2. Pleural effusion was less frequent with once-daily dosing than with twice-daily dosing (all grades, 18% versus 32%). Notably, none of the differences between the two schedules was statistically significant. Compared with the 70 mg twice daily, dasatinib 140 mg once daily had similar overall efficacy and safety in patients with imatinib-resistant or intolerant Ph+ ALL. (clinicaltrials.gov identifier: NCT00123487).
American Journal of Hematology 03/2010; 85(3):164-70. · 4.67 Impact Factor
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Neil P Shah,
Dong-Wook Kim,
Hagop Kantarjian,
Philippe Rousselot,
Pedro Enrique Dorlhiac Llacer,
Alicia Enrico,
Jorge Vela-Ojeda,
Richard T Silver,
Hanna Jean Khoury,
Martin C Müller,
Alexandre Lambert,
Yousif Matloub,
Andreas Hochhaus
[show abstract]
[hide abstract]
ABSTRACT: Dasatinib 100 mg once daily achieves intermittent BCR-ABL kinase inhibition and is approved for chronic-phase chronic myeloid leukemia patients resistant or intolerant to imatinib. To better assess durability of response to and tolerability of dasatinib, data from a 2-year minimum follow-up for a dose-optimization study in chronic-phase chronic myeloid leukemia are reported here.
In a phase 3 study, 670 chronic-phase chronic myeloid leukemia patients with resistance, intolerance, or suboptimal response to imatinib were randomized to dasatinib 100 mg once-daily, 50 mg twice-daily, 140 mg once-daily, or 70 mg twice-daily.
Data from a 2-year minimum follow-up demonstrate that dasatinib 100 mg once daily achieves major cytogenetic response and complete cytogenetic response rates comparable to those in the other treatment arms, and reduces the frequency of key side effects. Comparable 2-year progression-free survival and overall survival rates were observed (80% and 91%, respectively, for 100 mg once daily, and 75%-76% and 88%-94%, respectively, in other arms). Complete cytogenetic responses were achieved rapidly, typically by 6 months. In patients treated with dasatinib 100 mg once daily for 6 months without complete cytogenetic response, the likelihood of achieving such a response by 2 years was 50% for patients who had achieved a partial cytogenetic response, and only 8% or less for patients with minor, minimal, or no cytogenetic response. Less than 3% of patients suffered disease transformation to accelerated or blast phase.
Intermittent kinase inhibition can achieve rapid and durable responses, indistinguishable from those achieved with more continuous inhibition.
Haematologica 02/2010; 95(2):232-40. · 6.42 Impact Factor
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Neil P Shah
Blood 12/2009; 114(24):4914-5. · 9.90 Impact Factor
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ABSTRACT: A clonal cytogenetic abnormality was observed in Philadelphia chromosome-negative bone marrow cells of 6/27 chronic myeloid leukemia patients (+8 in 4, -7 in 1, and 20q- in 1) with dasatinib-induced remissions. The X-linked human androgen receptor gene assay demonstrated clonality in one additional patient. Single nucleotide polymorphism array analysis revealed somatic uniparental disomy involving chromosome 17(p12-pter) in another patient. The TP53 gene had a 5' splice site deletion of exon 6 that caused alternative splicing, frame shifting and introduction of a premature stop codon. After three years, no patient developed myelodysplastic syndrome or acute myeloid leukemia.
Leukemia research 10/2009; 34(6):708-13. · 2.36 Impact Factor
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Hagop Kantarjian,
Ricardo Pasquini,
Vincent Lévy,
Saengsuree Jootar,
Jerzy Holowiecki,
Nelson Hamerschlak,
Timothy Hughes,
Eric Bleickardt,
David Dejardin,
Jorge Cortes, Neil P Shah
[show abstract]
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ABSTRACT: In patients with chronic-phase chronic myeloid leukemia (CP-CML), imatinib resistance is of increasing importance. Imatinib dose escalation was the main treatment option before dasatinib, which has 325-fold more potent inhibition than imatinib against unmutated Bcr-Abl in vitro. Data with a minimum of 2 years of follow-up were available for the current study of dasatinib and high-dose imatinib in CP-CML resistant to imatinib at daily doses from 400 mg to 600 mg.
A phase 2, open-label study was initiated of 150 patients with imatinib-resistant CP-CML who were randomized (2:1) to receive either dasatinib 70 mg twice daily (n=101) or high-dose imatinib 800 mg (400 mg twice daily; n=49).
At a minimum follow-up of 2 years, dasatinib demonstrated higher rates of complete hematologic response (93% vs 82%; P=.034), major cytogenetic response (MCyR) (53% vs 33%; P=.017), and complete cytogenetic response (44% vs 18%; P=.0025). At 18 months, the MCyR was maintained in 90% of patients on the dasatinib arm and in 74% of patients on the high-dose imatinib arm. Major molecular response rates also were more frequent with dasatinib than with high-dose imatinib (29% vs 12%; P=.028). The estimated progression-free survival also favored dasatinib (unstratified log-rank test; P=.0012).
After 2 years of follow-up, dasatinib demonstrated durable responses and improved response and progression-free survival rates relative to high-dose imatinib.
Cancer 07/2009; 115(18):4136-47. · 4.77 Impact Factor
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ABSTRACT: Imatinib is an inhibitor of the Abl tyrosine kinase domain that is effective in the treatment of chronic myelogenic leukemia. Although imatinib binds tightly to the Abl kinase domain, its affinity for the closely related kinase domain of c-Src is at least 2,000-fold lower. Imatinib recognition requires a specific inactive conformation of the kinase domain, in which a conserved Asp-Phe-Gly (DFG) motif is flipped with respect to the active conformation. The inability of c-Src to readily adopt this flipped DFG conformation was thought to underlie the selectivity of imatinib for Abl over c-Src. Here, we present a series of inhibitors (DSA compounds) that are based on the core scaffold of imatinib but which bind with equally high potency to c-Src and Abl. The DSA compounds bind to c-Src in the DFG-flipped conformation, as confirmed by crystal structures and kinetic analysis. The origin of the high affinity of these compounds for c-Src is suggested by the fact that they also inhibit clinically relevant Abl variants bearing mutations in a structural element, the P-loop, that normally interacts with the phosphate groups of ATP but is folded over a substructure of imatinib in Abl. Importantly, several of the DSA compounds block the growth of Ba/F3 cells harboring imatinib-resistant BCR-ABL mutants, including the Thr315Ile "gatekeeper" mutation, but do not suppress the growth of parental Ba/F3 cells.
Cancer Research 04/2009; 69(6):2384-92. · 7.86 Impact Factor
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ABSTRACT: The BCR-ABL inhibitor dasatinib achieves clinical remissions in chronic myeloid leukemia (CML) patients using a dosing schedule that achieves potent but transient BCR-ABL inhibition. In vitro, transient potent BCR-ABL inhibition with either dasatinib or imatinib is cytotoxic to CML cell lines, as is transient potent EGFR inhibition with erlotinib in a lung cancer cell line. Cytotoxicity correlates with the magnitude as well as the duration of kinase inhibition. Moreover, cytotoxicity with transient potent target inhibition is equivalent to prolonged target inhibition and in both cases is associated with BIM activation and rescued by BCL-2 overexpression. In CML patients receiving dasatinib once daily, response correlates with the magnitude of BCR-ABL kinase inhibition, thereby demonstrating the potential clinical utility of intermittent potent kinase inhibitor therapy.
Cancer cell 01/2009; 14(6):485-93. · 25.29 Impact Factor
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Neil P Shah,
Hagop M Kantarjian,
Dong-Wook Kim,
Delphine Réa,
Pedro E Dorlhiac-Llacer,
Jorge H Milone,
Jorge Vela-Ojeda,
Richard T Silver,
H Jean Khoury,
Aude Charbonnier,
Nina Khoroshko,
Ronald L Paquette,
Michael Deininger,
Robert H Collins,
Irma Otero,
Timothy Hughes,
Eric Bleickardt,
Lewis Strauss,
Stephen Francis,
Andreas Hochhaus
[show abstract]
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ABSTRACT: Dasatinib is a BCR-ABL inhibitor, 325-fold more potent than imatinib against unmutated BCR-ABL in vitro. Phase II studies have demonstrated efficacy and safety with dasatinib 70 mg twice daily in chronic-phase (CP) chronic myelogenous leukemia (CML) after imatinib treatment failure. In phase I, responses occurred with once-daily administration despite only intermittent BCR-ABL inhibition. Once-daily treatment resulted in less toxicity, suggesting that toxicity results from continuous inhibition of unintended targets. Here, a dose- and schedule-optimization study is reported.
In this open-label phase III trial, 670 patients with imatinib-resistant or -intolerant CP-CML were randomly assigned 1:1:1:1 between four dasatinib treatment groups: 100 mg once daily, 50 mg twice daily, 140 mg once daily, or 70 mg twice daily.
With minimum follow-up of 6 months (median treatment duration, 8 months; range, < 1 to 15 months), marked and comparable hematologic (complete, 86% to 92%) and cytogenetic (major, 54% to 59%; complete, 41% to 45%) response rates were observed across the four groups. Time to and duration of cytogenetic response were similar, as was progression-free survival (8% to 11% of patients experienced disease progression or died). Compared with the approved 70-mg twice-daily regimen, dasatinib 100 mg once daily resulted in significantly lower rates of pleural effusion (all grades, 7% v 16%; P = .024) and grade 3 to 4 thrombocytopenia (22% v 37%; P = .004), and fewer patients required dose interruption (51% v 68%), reduction (30% v 55%), or discontinuation (16% v 23%).
Dasatinib 100 mg once daily retains the efficacy of 70 mg twice daily with less toxicity. Intermittent target inhibition with tyrosine kinase inhibitors may preserve efficacy and reduce adverse events.
Journal of Clinical Oncology 08/2008; 26(19):3204-12. · 18.37 Impact Factor
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Neil P Shah
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ABSTRACT: Tyrosine kinase inhibitor (TKI) therapy has impacted the natural course of chronic myelogenous leukemia (CML), because patients diagnosed as having chronic-phase disease can experience long-lasting responses. However, for patients with advanced CML (accelerated and blast phases), the efficacy of all current therapies is reduced. For these patients, allogeneic stem cell transplantation remains the preferred treatment if a donor is available, although TKIs play a valuable role as a bridging therapy. For patients with accelerated-phase CML, imatinib, dasatinib, and nilotinib have been shown to produce meaningful rates of hematologic and cytogenetic response. Imatinib and dasatinib are also approved for blast-phase CML. Studies with the newer agents have involved heavily pretreated patients; however, response rates have been at least comparable to those achieved with imatinib in previous studies. Therefore, these newer, more potent TKIs will probably be more likely to induce a deep response in previously untreated patients. Moreover, because fewer mechanisms appear to exist for secondary resistance to dasatinib and nilotinib, reducing the potential for disease to escape TKI therapy, these agents may result in improved longer-term outcomes. However, BCR-ABL-independent pathways may also become more important, indicating that other therapeutic targets may also have a future role in managing patients with advanced CML.
Journal of the National Comprehensive Cancer Network: JNCCN 03/2008; 6 Suppl 2:S31-S36. · 4.41 Impact Factor
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Neil P Shah
Clinical Cancer Research 10/2007; 13(18 Pt 1):5229-31. · 7.74 Impact Factor
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ABSTRACT: Molecularly targeted kinase inhibitor cancer therapies are currently administered sequentially rather than simultaneously. We addressed the potential long-term impact of this strategy in patients with chronic myelogenous leukemia (CML), which is driven by the fusion oncogene BCR-ABL. Analysis of BCR-ABL genotypes in CML patients who relapsed after sequential treatment with the ABL inhibitors imatinib and dasatinib revealed evolving resistant BCR-ABL kinase domain mutations in all cases. Twelve patients relapsed with the pan-resistant T315I mutation, whereas 6 patients developed novel BCR-ABL mutations predicted to retain sensitivity to imatinib based on in vitro studies. Three of these patients were retreated with imatinib (or the chemically related compound nilotinib) and responded; however, selection for compound mutants (2 or 3 BCR-ABL mutations in the same molecule) can substantially limit the potential effectiveness of retreating patients with inhibitors that have previously failed. Furthermore, drug-resistant mutations, when compounded, can increase oncogenic potency relative to the component mutants in transformation assays. The Aurora kinase inhibitor VX-680, currently under clinical evaluation based on its activity against the T315I mutation, is also effective against the other commonly detected dasatinib-resistant mutation in our analysis, V299L. Our findings demonstrate the potential hazards of sequential kinase inhibitor therapy and suggest a role for a combination of ABL kinase inhibitors, perhaps including VX-680, to prevent the outgrowth of cells harboring drug-resistant BCR-ABL mutations.
Journal of Clinical Investigation 10/2007; 117(9):2562-9. · 15.39 Impact Factor
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Andreas Hochhaus,
Hagop M Kantarjian,
Michele Baccarani,
Jeffrey H Lipton,
Jane F Apperley,
Brian J Druker,
Thierry Facon,
Stuart L Goldberg,
Francisco Cervantes,
Dietger Niederwieser,
Richard T Silver,
Richard M Stone,
Timothy P Hughes,
Martin C Muller,
Rana Ezzeddine,
Athena M Countouriotis, Neil P Shah
[show abstract]
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ABSTRACT: Although imatinib induces marked responses in patients with chronic myeloid leukemia (CML), resistance is increasingly problematic, and treatment options for imatinib-resistant or -intolerant CML are limited. Dasatinib, a novel, highly potent, oral, multitargeted kinase inhibitor of BCR-ABL and SRC family kinases, induced cytogenetic responses in a phase 1 study in imatinib-resistant or -intolerant CML and was well tolerated. Initial results are presented from a phase 2 study of 186 patients with imatinib-resistant or -intolerant chronic-phase CML (CML-CP) designed to further establish the efficacy and safety of dasatinib (70 mg twice daily). At 8-months' follow-up, dasatinib induced notable responses, with 90% and 52% of patients achieving complete hematologic and major cytogenetic responses (MCyR), respectively. Responses were long lasting: only 2% of patients achieving MCyR progressed or died. Importantly, comparable responses were achieved by patients carrying BCR-ABL mutations conferring imatinib resistance. Dasatinib also induced molecular responses, reducing BCR-ABL/ABL transcript ratios from 66% at baseline to 2.6% at 9 months. Nonhematologic adverse events were generally mild to moderate, and most cytopenias were effectively managed with dose modifications. Cross-intolerance with imatinib was not evident. To conclude, dasatinib induces notable responses in imatinib-resistant or -intolerant CML-CP, is well tolerated, and represents a promising therapeutic option for these patients. This trial was registered at www.clinicaltrials.gov as CA180013.
Blood 04/2007; 109(6):2303-9. · 9.90 Impact Factor
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Neil P Shah
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ABSTRACT: Dasatinib is an orally bioavailable potent inhibitor of multiple tyrosine kinases, including ABL and SRC. Preclinical studies have shown dasatinib to be a much more potent inhibitor of BCR-ABL than imatinib is, and to harbor efficacy against nearly all imatinib-resistant BCR-ABL mutants. Phase I clinical studies have been conducted in imatinib-resistant and -intolerant chronic myeloid leukemia and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia. No dose-limiting toxicity was observed at doses that harbored substantial clinical efficacy. Multinational phase II studies have confirmed the phase I experience and have led to accelerated approval by the U.S. Food and Drug Administration for the treatment of imatinib-resistant and -intolerant chronic myeloid leukemia as well as its full approval for the treatment of therapy-resistant Ph+ acute lymphoblastic leukemia.
Drugs of today (Barcelona, Spain: 1998) 02/2007; 43(1):5-12. · 1.28 Impact Factor
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ABSTRACT: Mastocytosis is associated with an activating mutation in the KIT oncoprotein (KITD816V) that results in autophosphorylation of the KIT receptor in a ligand-independent manner. This mutation is inherently resistant to imatinib and, to date, there remains no effective curative therapy for systemic mastocytosis associated with KITD816V. Dasatinib (BMS-354825) is a novel orally bioavailable SRC/ABL inhibitor that has activity against multiple imatinib-resistant BCR-ABL isoforms in vitro that is presently showing considerable promise in early-phase clinical trials of chronic myeloid leukemia (CML). Pharmacokinetic analysis suggests that high nanomolar concentrations of dasatinib can be achieved safely in humans. In this study, we demonstrate significant inhibitory activity of dasatinib against both wild-type KIT and the KITD816V mutation in the nanomolar range in in vitro and cell-based kinase assays. Additionally, dasatinib leads to growth inhibition of a KITD816V-harboring human masto-cytosis cell line. Significantly, dasatinib selectively kills primary neoplastic bone marrow mast cells from patients with systemic mastocytosis while sparing other hematopoietic cells. Computer modeling suggests that the KITD816V mutation destabilizes the inactive conformation of the KIT activation loop to which imatinib binds, but it is not predicted to impair binding of KIT by dasatinib. Based upon our results, further evaluation of dasatinib for the treatment of systemic masto-cytosis in clinical trials is warranted. Moreover, dasatinib may be of clinical utility in other disease settings driven by activating KIT mutations.
Blood 08/2006; 108(1):286-91. · 9.90 Impact Factor
