ABL Mutations in Late Chronic Phase Chronic Myeloid Leukemia Patients With Up-Front Cytogenetic Resistance to Imatinib Are Associated With a Greater Likelihood of Progression to Blast Crisis and Shorter Survival: A Study by the GIMEMA Working Party on Chronic Myeloid Leukemia

Soverini, Simona; Martinelli, Giovanni; Rosti, Gianantonio; Bassi, Simona; Amabile, Marilina; Poerio, Angela; Giannini, Barbara; Trabacchi, Elena; Castagnetti, Fausto; Testoni, Nicoletta; Luatti, Simona; Vivo, Antonio De; Cilloni, Daniela; Izzo, Barbara; Fava, Milena; Abruzzese, Elisabetta; Alberti, Daniele; Pane, Fabrizio; Saglio, Giuseppe; Baccarani, Michele

doi:10.1200/jco.2005.05.531

Cited by 344 publications

(263 citation statements)

References 37 publications

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“…23 The most common cause of secondary imatinib resistance is point mutations in BCR-ABL that prevent effective binding of imatinib but may retain kinase activity. [35][36][37][38][39] These mutations are clustered primarily within the kinase domain of BCR-ABL (ABL exons 4-10). 40 They exhibit differential relative resistance to imatinib in vitro.…”

Section: Imatinib Nilotinib Dasatinibmentioning

confidence: 99%

Optimizing therapy for patients with chronic myelogenous leukemia in chronic phase

Kantarjian

Cortés

Rosée

et al. 2010

Cancer

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Identification of BCR‐ABL as the defining leukemogenic event in chronic myelogenous leukemia (CML) revolutionized the treatment of the disease. Imatinib, a potent BCR‐ABL inhibitor, is the standard of care for the first‐line treatment of patients with chronic‐phase CML because of its high long‐term response rates and favorable tolerability profile compared with previous standard therapies. However, resistance to imatinib develops in 2% to 4% of patients annually. For patients with acquired cytogenetic resistance to standard‐dose imatinib (400 mg daily), imatinib dose escalation (600‐800 mg daily) is an excellent first option for managing patients and achieving cytogenetic responses. However, for patients with primary resistance to imatinib, hematologic disease recurrence, or emergent BCR‐ABL kinase domain mutations, imatinib dose escalation may not be sufficient to control the disease. For these patients, the potent second‐generation tyrosine kinase inhibitors dasatinib and nilotinib are available. Both agents provide effective therapeutic options for patients with imatinib resistance or intolerance. For the current overview, the authors reviewed the data supporting the use of both dasatinib and nilotinib in imatinib‐resistant or imatinib‐intolerant patients, and they have highlighted the future of CML therapy. Overall, the article is intended to offer physicians a comprehensive review of the current literature and to provide data supporting various treatment options for patients with CML throughout the course of imatinib therapy and beyond. Cancer 2010. © 2010 American Cancer Society.

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Section: Imatinib Nilotinib Dasatinibmentioning

confidence: 99%

Optimizing therapy for patients with chronic myelogenous leukemia in chronic phase

Kantarjian

Cortés

Rosée

et al. 2010

Cancer

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“…According to this model, CML blast crisis would be expected to occur only in patients with an imatinib-resistant disease or in those developing resistance during treatment. Indeed, a recent study from the GIMEMA Working Party on CML reported that the early detection of BCR/ABL mutations in CML chronic phase patients is associated with a greater likelihood of disease progression (Soverini et al, 2005). Interestingly, a direct correlation also seems to exist between levels of BCR/ABL activity and development of imatinib resistance (Schultheis et al, 2005;Barnes et al, 2005a).…”

Section: CML Bcr/abl and Imatinibmentioning

confidence: 99%

ReSETting PP2A tumour suppressor activity in blast crisis and imatinib-resistant chronic myelogenous leukaemia

Perrotti

Neviani

2006

Br J Cancer

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The deregulated kinase activity of p210-BCR/ABL oncoproteins, hallmark of chronic myelogenous leukaemia (CML), induces and sustains the leukaemic phenotype, and contributes to disease progression. Imatinib mesylate, a BCR/ABL kinase inhibitor, is effective in most of chronic phase CML patients. However, a significant percentage of CML patients develop resistance to imatinib and/or still progresses to blast crisis, a disease stage that is often refractory to imatinib therapy. Furthermore, there is compelling evidence indicating that the CML leukaemia stem cell is also resistant to imatinib. Thus, there is still a need for new drugs that, if combined with imatinib, will decrease the rate of relapse, fully overcome imatinib resistance and prevent blastic transformation of CML. We recently reported that the activity of the tumour suppressor protein phosphatase 2A (PP2A) is markedly inhibited in blast crisis CML patient cells and that molecular or pharmacologic re-activation of PP2A phosphatase led to growth suppression, enhanced apoptosis, impaired clonogenic potential and decreased in vivo leukaemogenesis of imatinib-sensitive and -resistant (T315I included) CML-BC patient cells and/or BCR/ABL þ myeloid progenitor cell lines. Thus, the combination of PP2A phosphatase-activating and BCR/ABL kinase-inhibiting drugs may represent a powerful therapeutic strategy for blast crisis CML patients.

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“…For a relatively few CML patients, resistance to imatinib is present before, or develops during treatment. [8][9][10][11] Several strategies are available to treat imatinib-resistant patients, including imatinib dose escalation, dose adjustment based on pharmacokinetic assessments and the use of novel TKIs ( Figure 1, Table 1). …”

Section: Introductionmentioning

confidence: 99%

Class effects of tyrosine kinase inhibitors in the treatment of chronic myeloid leukemia

2009

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Tyrosine kinase inhibitors have revolutionized the treatment of chronic myeloid leukemia (CML), offering patients several targeted therapeutic options that provide the possibility of sustained remissions and prolonged survival. With the availability of imatinib, nilotinib and dasatinib, physicians must weigh the efficacy and safety profile of each agent when choosing the best therapeutic option for individual patients. Each agent targets tyrosine kinases within the cell uniquely to cause the desired antiproliferative effect. In addition to inhibiting the BCR-ABL kinase, imatinib and nilotinib target the same array of other tyrosine kinases, including c-KIT and plateletderived growth factor receptor (PDGFR), albeit with differing potencies. While targeting BCR-ABL with the highest potency among approved agents in CML, dasatinib also targets a broad array of off-target kinases, including SRC family members, PDGFR and EPHB4. The differences in kinase inhibition profiles among these agents in vitro probably account for the differing clinical safety profiles of these agents. This paper reviews the various kinases inhibited by imatinib, nilotinib and dasatinib, and describes the potential impact of kinase inhibition on the efficacy and safety of each agent.

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ABL Mutations in Late Chronic Phase Chronic Myeloid Leukemia Patients With Up-Front Cytogenetic Resistance to Imatinib Are Associated With a Greater Likelihood of Progression to Blast Crisis and Shorter Survival: A Study by the GIMEMA Working Party on Chronic Myeloid Leukemia

Abstract: Our results show that, irrespective of the hematologic response, monitoring for emerging mutations in the first months of therapy may play a role in detecting patients with worse prognosis, for whom a revision of the therapeutic strategy should be considered.

Cited by 344 publications

References 37 publications

Optimizing therapy for patients with chronic myelogenous leukemia in chronic phase

Optimizing therapy for patients with chronic myelogenous leukemia in chronic phase

ReSETting PP2A tumour suppressor activity in blast crisis and imatinib-resistant chronic myelogenous leukaemia

Class effects of tyrosine kinase inhibitors in the treatment of chronic myeloid leukemia

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