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Pratap Neelakantan,
Gareth Gerrard,
Claire Lucas,
Dragana Milojkovic,
Philippa May,
Lihui Wang,
Christos Paliompeis,
Marco Bua,
Alistair Reid,
Katayoun Rezvani,
Stephen O'Brien,
Richard Clark, John Goldman,
David Marin
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ABSTRACT: Several groups have shown that that the BCR-ABL1 transcript level measured at 3 or 6 months after starting treatment with tyrosine kinase inhibitors strongly predicts for clinical outcomes for CML patients. In this work we asked whether the prognostic value of the 3-month transcript level could be improved by combining the 3- and 6- month results. We classified patients treated with imatinib and patients treated with dasatinib according to their transcript levels at 3 months and 6 months. The patients who met the 3-month landmark but failed the 6-month one had outcomes identical to those of patients who met both landmarks whereas the patients who failed the first landmark but met the second one had prognoses similar to those who failed both landmarks. In summary early intervention strategies can be based robustly just on the transcript level at 3 months. (ClinicalTrials.gov Identifier: NCT01460693).
Blood 02/2013; · 9.90 Impact Factor
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ABSTRACT: PURPOSE OF REVIEW: In this review, we analyze some of the topical issues in the clinical management of chronic myeloid leukaemia (CML). RECENT FINDINGS: In recent years, the management of CML patients has increased in complexity as molecular monitoring has brought to the clinical scene new therapeutic targets and the second-generation tyrosine kinase inhibitors have been licensed for first-line use. SUMMARY: In this article, we will try to answer some of the questions that a practising physician may face in clinical practice, such as: What should be the aim of therapy? What is the best front-line therapy? Which patients should receive an allogeneic stem cell transplant?
Current opinion in hematology 01/2013; · 5.19 Impact Factor
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Blood 12/2012; 120(25):5087-8. · 9.90 Impact Factor
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Haematologica 04/2012; 97(9):1444. · 6.42 Impact Factor
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Mary Alikian,
Gareth Gerrard,
Papagudi G Subramanian,
Katherine Mudge,
Pierre Foskett,
Jamshid Sorouri Khorashad,
Ai Chiin Lim,
David Marin,
Dragana Milojkovic,
Alistair Reid,
Katy Rezvani, John Goldman,
Jane Apperley,
Letizia Foroni
[show abstract]
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ABSTRACT: The introduction of tyrosine kinase inhibitors (TKIs), starting with imatinib and followed by second and third generation TKIs, has significantly changed the clinical management of patients with chronic myeloid leukemia (CML). Despite their unprecedented clinical success, a proportion of patients fail to achieve complete cytogenetic remission by 12 months of treatment (primary resistance) while others experience progressive resistance after an initial response (secondary resistance). BCR-ABL1 kinase domain (KD) mutations have been detected in a proportion of patients at the time of treatment failure, and therefore their identification and monitoring plays an important role in therapeutic decisions particularly when switching TKIs. When monitoring KD mutations in a clinical laboratory, the choice of method should take into account turnaround time, cost, sensitivity, specificity, and ability to accurately quantify the size of the mutant clone. In this article, we describe in a "manual" style the methods most widely used in our laboratory to monitor KD mutations in patients with CML including direct sequencing, D-HPLC, and pyrosequencing. Advantages, disadvantages, interpretation of results, and their clinical applications are reviewed for each method.
American Journal of Hematology 03/2012; 87(3):298-304. · 4.67 Impact Factor
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Aristeidis Chaidos,
Scott Patterson,
Richard Szydlo,
Mohammed Suhail Chaudhry,
Francesco Dazzi,
Edward Kanfer,
Donald McDonald,
David Marin,
Dragana Milojkovic,
Jiri Pavlu,
John Davis,
Amin Rahemtulla,
Katy Rezvani, John Goldman,
Irene Roberts,
Jane Apperley,
Anastasios Karadimitris
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ABSTRACT: Invariant natural killer T (iNKT) cells are powerful immunomodulatory cells that in mice regulate a variety of immune responses, including acute GVHD (aGVHD). However, their clinical relevance and in particular their role in clinical aGVHD are not known. We studied whether peripheral blood stem cell (PBSC) graft iNKT-cell dose affects on the occurrence of clinically significant grade II-IV aGVHD in patients (n = 57) undergoing sibling, HLA-identical allogeneic HSCT. In multivariate analysis, CD4(-) iNKT-cell dose was the only graft parameter to predict clinically significant aGVHD. The cumulative incidence of grade II-IV aGVHD in patients receiving CD4(-) iNKT-cell doses above and below the median were 24.2% and 71.4%, respectively (P = .0008); low CD4(-) iNKT-cell dose was associated with a relative risk of grade II-IV aGVHD of 4.27 (P = .0023; 95% CI, 1.68-10.85). Consistent with a role of iNKT cells in regulating aGVHD, in mixed lymphocyte reaction assays, CD4(-) iNKT cells effectively suppressed T-cell proliferation and IFN-γ secretion in a contact-dependent manner. In conclusion, higher doses of CD4(-) iNKT cells in PBSC grafts are associated with protection from aGVHD. This effect could be harnessed for prevention of aGVHD.
Blood 02/2012; 119(21):5030-6. · 9.90 Impact Factor
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Dragana Milojkovic,
Jane F Apperley,
Gareth Gerrard,
Amr R Ibrahim,
Richard Szydlo,
Marco Bua,
Alistair Reid,
Katayoun Rezvani,
Letizia Foroni, John Goldman,
David Marin
[show abstract]
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ABSTRACT: Second-generation tyrosine kinase inhibitors (2G-TKIs) are effective at inducing complete cytogenetic responses (CCyRs) in approximately half of chronic myeloid leukemia patients treated while still in the chronic phase and after failing imatinib. It is less clear whether these responses are durable. In the present study, we report the clinical outcome of 119 patients who received a 2G-TKI as second-line treatment while still in the chronic phase. In an intention-to-treat analysis, the 4-year probabilities of overall and event-free survival were 81.9% and 35.3%, respectively. Sixty-two patients discontinued the initial 2G-TKI because of resistance or intolerance. To further explore the durability of cytogenetic responses, irrespective of the need for a third-line TKI, we used the concept of "current CCyR-survival" (c-CCyRS). The c-CCyRS at 4 years was 54.4%. After introduction of a 2G-TKI, 77 patients had a 3-month BCR-ABL1/ABL1 transcript ratio of ≤ 10% and had significantly superior overall survival (91.3% vs 72.1%, P = .02), event-free survival (49.3% vs 13.0%, P < .001), and c-CCyRS (67.2% vs 11.2%, P = .0001) compared with the 33 patients with ratios > 10%. The 3-month molecular response was the only independent predictor for overall survival. Using an intention-to-treat analysis, we have shown that the responses to second-line therapies are durable. Patients destined to fare poorly can be identified early during therapy.
Blood 12/2011; 119(8):1838-43. · 9.90 Impact Factor
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ABSTRACT: Imatinib induces a durable response in most patients with Philadelphia chromosome-positive chronic myeloid leukemia, but it is currently unclear whether imatinib reduces the leukemic stem cell (LSC) burden, which may be an important step toward enabling safe discontinuation of therapy. In this article, we use mathematical models of BCR-ABL levels to make inferences on the dynamics of LSCs.
Patients with at least 1 BCR-ABL transcript measurement on imatinib were included (N = 477). Maximum likelihood methods were used to test 3 potential hypotheses of the dynamics of BCR-ABL transcripts on imatinib therapy: (i) monoexponential, in which there is little, if any, decline in BCR-ABL transcripts; (ii) biexponential, in which patients have a rapid initial decrease in BCR-ABL transcripts followed by a more gradual response; and (iii) triexponential, in which patients first exhibit a biphasic decline but then have a third phase when BCR-ABL transcripts increase rapidly.
We found that most patients treated with imatinib exhibit a biphasic decrease in BCR-ABL transcript levels, with a rapid decrease during the first few months of treatment, followed by a more gradual decrease that often continues over many years.
We show that the only hypothesis consistent with current data on progenitor cell turnover and with the long-term, gradual decrease in the BCR-ABL levels seen in most patients is that these patients exhibit a continual, gradual reduction of the LSCs. This observation may explain the ability to discontinue imatinib therapy without relapse in some cases.
Clinical Cancer Research 09/2011; 17(21):6812-21. · 7.74 Impact Factor
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Amr R Ibrahim,
Lina Eliasson,
Jane F Apperley,
Dragana Milojkovic,
Marco Bua,
Richard Szydlo,
Francois-Xavier Mahon,
Kasia Kozlowski,
Christos Paliompeis,
Letizia Foroni,
Jamshid S Khorashad,
Alex Bazeos,
Mathieu Molimard,
Alistair Reid,
Katayoun Rezvani,
Gareth Gerrard, John Goldman,
David Marin
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ABSTRACT: We studied the relation between adherence to imatinib measured with microelectronic monitoring systems and the probabilities of losing a complete cytogenetic response (CCyR) and of imatinib failure in 87 CCyR chronic myeloid leukemia patients receiving long-term therapy. We included in our analysis the most relevant prognostic factors described to date. On multivariate analysis, the adherence rate and having failed to achieve a major molecular response were the only independent predictors for loss of CCyR and discontinuation of imatinib therapy. The 23 patients with an adherence rate less than or equal to 85% had a higher probability of losing their CCyR at 2 years (26.8% vs 1.5%, P = .0002) and a lower probability of remaining on imatinib (64.5% vs 90.6%, P = .006) than the 64 patients with an adherence rate more than 85%. In summary, we have shown that poor adherence is the principal factor contributing to the loss of cytogenetic responses and treatment failure in patients on long-term therapy.
Blood 02/2011; 117(14):3733-6. · 9.90 Impact Factor
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Richard A Van Etten,
Steffen Koschmieder,
Francois Delhommeau,
Danilo Perrotti,
Tessa Holyoake,
Animesh Pardanani,
Ruben Mesa,
Tony Green,
Amr R Ibrahim,
Tariq Mughal,
Robert Peter Gale, John Goldman
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ABSTRACT: This review focuses on topical issues in the biology and treatment of the myeloproliferative neoplasms (MPNs). Studies in transgenic mice suggest that BCR-ABL1 reduces the fraction of self-renewing 'leukemic' stem cells in the bone marrow but that some of these cells survive treatment with imatinib. This also seems to operate in humans. Data from models also strongly support the notion that JAK2(V617F) can initiate and sustain MPNs in mice; relevance to disease in humans is less clear. These data also support the hypothesis that level of JAK2(V617F) expression influences the MPN phenotype: higher levels favor erythrocytosis whereas lower levels favor thrombocytosis. Although TET2-mutations were thought to precede JAK2(V617F) in some persons with MPNs, it now appears that TET2 mutations may occur after JAK2(V617F). Further understanding of signal-transduction pathways activated in chronic myeloid leukemia suggests various possible targets for new therapies including the WNT/beta catenin, notch and hedgehog pathways. Finally, the clinical role of the new JAK2- and BCR-ABL1-inhibitors is considered. Much further progress is likely in several of these areas soon.
Haematologica 01/2011; 96(4):590-601. · 6.42 Impact Factor
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Gareth Gerrard,
Katherine Mudge,
Rebecca Stewart,
Pierre Foskett,
David Stevens,
Jamshid S Khorashad,
Richard Szydlo,
Katy Rezvani,
David Marin,
Alistair Reid,
Jane Apperley, John Goldman,
Letizia Foroni
American Journal of Hematology 12/2010; 86(3):313-5. · 4.67 Impact Factor
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Aya Kuwabara,
Anna Babb,
Amr Ibrahim,
Dragana Milojkovic,
Jane Apperley,
Marco Bua,
Alistair Reid,
Letizia Foroni,
Katayoun Rezvani, John Goldman,
David Marin
Blood 08/2010; 116(6):1014-6. · 9.90 Impact Factor
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Takahiro Ito,
Hyog Young Kwon,
Bryan Zimdahl,
Kendra L Congdon,
Jordan Blum,
William E Lento,
Chen Zhao,
Anand Lagoo,
Gareth Gerrard,
Letizia Foroni, John Goldman,
Harriet Goh,
Soo-Hyun Kim,
Dong-Wook Kim,
Charles Chuah,
Vivian G Oehler,
Jerald P Radich,
Craig T Jordan,
Tannishtha Reya
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ABSTRACT: Chronic myelogenous leukaemia (CML) can progress from a slow growing chronic phase to an aggressive blast crisis phase, but the molecular basis of this transition remains poorly understood. Here we have used mouse models of CML to show that disease progression is regulated by the Musashi-Numb signalling axis. Specifically, we find that the chronic phase is marked by high levels of Numb expression whereas the blast crisis phase has low levels of Numb expression, and that ectopic expression of Numb promotes differentiation and impairs advanced-phase disease in vivo. As a possible explanation for the decreased levels of Numb in the blast crisis phase, we show that NUP98-HOXA9, an oncogene associated with blast crisis CML, can trigger expression of the RNA-binding protein Musashi2 (Msi2), which in turn represses Numb. Notably, loss of Msi2 restores Numb expression and significantly impairs the development and propagation of blast crisis CML in vitro and in vivo. Finally we show that Msi2 expression is not only highly upregulated during human CML progression but is also an early indicator of poorer prognosis. These data show that the Musashi-Numb pathway can control the differentiation of CML cells, and raise the possibility that targeting this pathway may provide a new strategy for the therapy of aggressive leukaemias.
Nature 08/2010; 466(7307):765-8. · 36.28 Impact Factor
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David Marin,
Alexandra Bazeos,
Francois-Xavier Mahon,
Lina Eliasson,
Dragana Milojkovic,
Marco Bua,
Jane F Apperley,
Richard Szydlo,
Ritti Desai,
Kasia Kozlowski,
Christos Paliompeis,
Victoria Latham,
Letizia Foroni,
Mathieu Molimard,
Alistair Reid,
Katy Rezvani,
Hugues de Lavallade,
Cristina Guallar, John Goldman,
Jamshid S Khorashad
[show abstract]
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ABSTRACT: There is a considerable variability in the level of molecular responses achieved with imatinib therapy in patients with chronic myeloid leukemia (CML). These differences could result from variable therapy adherence.
Eighty-seven patients with chronic-phase CML treated with imatinib 400 mg/d for a median of 59.7 months (range, 25 to 104 months) who had achieved complete cytogenetic response had adherence monitored during a 3-month period by using a microelectronic monitoring device. Adherence was correlated with levels of molecular response. Other factors that could influence outcome were also analyzed.
Median adherence rate was 98% (range, 24% to 104%). Twenty-three patients (26.4%) had adherence <or= 90%; in 12 of these patients (14%), adherence was <or= 80%. There was a strong correlation between adherence rate (<or= 90% or > 90%) and the 6-year probability of a 3-log reduction (also known as major molecular response [MMR]) in BCR-ABL1 transcripts (28.4% v 94.5%; P < .001) and also complete molecular response (CMR; 0% v 43.8%; P = .002). Multivariate analysis identified adherence (relative risk [RR], 11.7; P = .001) and expression of the molecular human organic cation transporter-1 (RR, 1.79; P = .038) as the only independent predictors for MMR. Adherence was the only independent predictor for CMR. No molecular responses were observed when adherence was <or= 80% (P < .001). Patients whose imatinib doses were increased had poor adherence (86.4%). In this latter population, adherence was the only independent predictor for inability to achieve an MMR (RR, 17.66; P = .006).
In patients with CML treated with imatinib for some years, poor adherence may be the predominant reason for inability to obtain adequate molecular responses.
Journal of Clinical Oncology 04/2010; 28(14):2381-8. · 18.37 Impact Factor
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Michele Baccarani,
Jorge Cortes,
Fabrizio Pane,
Dietger Niederwieser,
Giuseppe Saglio,
Jane Apperley,
Francisco Cervantes,
Michael Deininger,
Alois Gratwohl,
François Guilhot,
Andreas Hochhaus,
Mary Horowitz,
Timothy Hughes,
Hagop Kantarjian,
Richard Larson,
Jerald Radich,
Bengt Simonsson,
Richard T Silver, John Goldman,
Rudiger Hehlmann
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ABSTRACT: To review and update the European LeukemiaNet (ELN) recommendations for the management of chronic myeloid leukemia with imatinib and second-generation tyrosine kinase inhibitors (TKIs), including monitoring, response definition, and first- and second-line therapy.
These recommendations are based on a critical and comprehensive review of the relevant papers up to February 2009 and the results of four consensus conferences held by the panel of experts appointed by ELN in 2008.
Cytogenetic monitoring was required at 3, 6, 12, and 18 months. Molecular monitoring was required every 3 months. On the basis of the degree and the timing of hematologic, cytogenetic, and molecular results, the response to first-line imatinib was defined as optimal, suboptimal, or failure, and the response to second-generation TKIs was defined as suboptimal or failure.
Initial treatment was confirmed as imatinib 400 mg daily. Imatinib should be continued indefinitely in optimal responders. Suboptimal responders may continue on imatinb, at the same or higher dose, or may be eligible for investigational therapy with second-generation TKIs. In instances of imatinib failure, second-generation TKIs are recommended, followed by allogeneic hematopoietic stem-cell transplantation only in instances of failure and, sometimes, suboptimal response, depending on transplantation risk.
Journal of Clinical Oncology 11/2009; 27(35):6041-51. · 18.37 Impact Factor
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ABSTRACT: Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by a triphasic clinical course, the morphologic expansion of a terminally differentiated myeloid cell and the presence of the BCR-ABL1 fusion gene, the hallmark of CML. The fusion gene is usually, but not always, associated with a Philadelphia chromosome, the result of a reciprocal exchange of genetic material between chromosome 22 and chromosome 9, which leads to the production of the activated BCR-ABL1 gene and oncoprotein. The breakpoint in the BCR gene occurs commonly downstream of exons e13 or e14 (M-BCR) and less frequently downstream of exons e1 and e2 (m-BCR). Less than 1% of cases carry a breakpoint downstream of exon 6 or 8 (“variant fusion genes”) or exon 19 (μ-BCR). Breakpoints in the ABL1 gene cluster upstream of exon a2 (or of exon a3 in less than 5% of patients with CML). Conventional cytogenetic, fluorescence in situ hybridization, and molecular testing for the BCR-ABL1 fusion gene are key investigations for the diagnosis and monitoring of CML. Treatment using tyrosine kinase inhibitors has revolutionized the management of CML with hematologic and cytogenetic response within 12–18 months observed in >85% of patients. Nevertheless, between 15 and 20% of patients may evolve to blastic phase. Measurement of low level or “minimal” residual disease using molecular tests is becoming the gold-standard approach to measure response to therapy due to its higher sensitivity compared to other routine techniques. The technical aspects and clinical applications of molecular monitoring will be the main focus of this article. Am. J. Hematol., 2009. © 2009 Wiley-Liss, Inc.
American Journal of Hematology 05/2009; 84(8):517 - 522. · 4.67 Impact Factor
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[show abstract]
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ABSTRACT: Chronic myeloid leukemia (CML) is a myeloproliferative disorder characterized by a triphasic clinical course, the morphologic expansion of a terminally differentiated myeloid cell and the presence of the BCR-ABL1 fusion gene, the hallmark of CML. The fusion gene is usually, but not always, associated with a Philadelphia chromosome, the result of a reciprocal exchange of genetic material between chromosome 22 and chromosome 9, which leads to the production of the activated BCR-ABL1 gene and oncoprotein. The breakpoint in the BCR gene occurs commonly downstream of exons e13 or e14 (M-BCR) and less frequently downstream of exons e1 and e2 (m-BCR). Less than 1% of cases carry a breakpoint downstream of exon 6 or 8 ("variant fusion genes") or exon 19 (mu-BCR). Breakpoints in the ABL1 gene cluster upstream of exon a2 (or of exon a3 in less than 5% of patients with CML). Conventional cytogenetic, fluorescence in situ hybridization, and molecular testing for the BCR-ABL1 fusion gene are key investigations for the diagnosis and monitoring of CML. Treatment using tyrosine kinase inhibitors has revolutionized the management of CML with hematologic and cytogenetic response within 12-18 months observed in >85% of patients. Nevertheless, between 15 and 20% of patients may evolve to blastic phase. Measurement of low level or "minimal" residual disease using molecular tests is becoming the gold-standard approach to measure response to therapy due to its higher sensitivity compared to other routine techniques. The technical aspects and clinical applications of molecular monitoring will be the main focus of this article.
American Journal of Hematology 05/2009; 84(8):517-22. · 4.67 Impact Factor
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Jamshid Sorouri Khorashad,
Simon Wagner,
Liat Greener,
David Marin,
Alistair Reid,
Dragana Milojkovic,
Hetal Patel,
Shaun Willimott,
Katy Rezvani,
Gareth Gerrard,
Sandra Loaiza,
John Davis, John Goldman,
Junia Melo,
Jane Apperley,
Letizia Foroni
[show abstract]
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ABSTRACT: Imatinib is currently the first line therapy for newly diagnosed patients with chronic myeloid leukemia. However, 20-25% of patients do not achieve durable complete cytogenetic responses. The mechanism underlying this primary resistance is unknown, but variations in BCR-ABL1 kinase activity may play a role and can be investigated by measuring the autophosphorylation levels of BCR-ABL1 or of a surrogate target such as Crkl. In this study we used flow cytometry to investigate the in vitro inhibition of Crkl phosphorylation by imatinib in CD34(+) cells in diagnostic samples from two groups of patients distinguished by their cytogenetic response. No difference in inhibition of Crkl phosphorylation was observed in the two groups. The observation that increasing the dose of imatinib in vivo did not increase the level of cytogenetic response in some non-responders suggests that in at least a proportion of patients imatinib resistance may be due to activation of BCR-ABL1-independent pathway.
Haematologica 05/2009; 94(6):861-4. · 6.42 Impact Factor
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Andreas Hochhaus,
Brian Druker,
Charles Sawyers,
Francois Guilhot,
Charles A Schiffer,
Jorge Cortes,
Dietger W Niederwieser,
Carlo Gambacorti-Passerini,
Carlo Gambacorti,
Richard M Stone, John Goldman,
Thomas Fischer,
Stephen G O'Brien,
Jose J Reiffers,
Manisha Mone,
Tillmann Krahnke,
Moshe Talpaz,
Hagop M Kantarjian
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ABSTRACT: Imatinib mesylate, a targeted inhibitor of BCR-ABL tyrosine kinase, is the standard of care for chronic myeloid leukemia (CML). A phase 2 trial of imatinib in late chronic-phase (CP) CML after interferon-alpha (IFNalpha) failure enrolled 532 patients, 454 with a confirmed diagnosis of CP CML. Median time from diagnosis was 34 months; median duration of imatinib treatment was 65 months. Cumulative best rates of major cytogenetic response (MCyR) and complete cytogenetic response (CCyR) were 67% and 57%, respectively. At the 5-year landmark, 184 (41%) of the 454 patients are in CCyR. At more than 6 years, 199 (44%) of the 454 patients remain on imatinib. Most responses occurred within 12 months of starting imatinib; however, some patients achieved initial MCyR and CCyR more than 5 years after imatinib initiation. Estimated rates of freedom from progression to accelerated phase (AP) and blastic phase (BP) and overall survival at 6 years were 61% and 76%, respectively. Both freedom from progression to AP/BP and overall survival (OS) were associated with cytogenetic response level at 12 months. No increase in rates of serious adverse events was observed with continuous use of imatinib for up to 6.5 years, compared with earlier time points. Imatinib continues to be an effective and safe therapy for patients with CP CML after failure of IFN.
Blood 03/2008; 111(3):1039-43. · 9.90 Impact Factor
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John Goldman
Leukemia and Lymphoma 01/2008; 48(12):2287-8. · 2.58 Impact Factor
