Frequency of Major Molecular Responses to Imatinib or Interferon Alfa plus Cytarabine in Newly Diagnosed Chronic Myeloid Leukemia

Hughes, Toby; Kaeda, Jaspal; Branford, Susan; Rudzki, Zbigniew; Hochhaus, Andreas; Hensley, Martee L.; Gathmann, Insa; Bolton, Ann E.; Hoomissen, Iris C. van; Goldman, John M.; Radich, Jerald P.

doi:10.1056/nejmoa030513

Cited by 1,095 publications

(896 citation statements)

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“…3). 21 The MMR rate was higher in patients who achieved a CCyR (57% for imatinib vs 24% for IFN; P ¼ .003). After 6 years of imatinib therapy, long-term response rates remained high.…”

Section: Imatinib Nilotinib Dasatinibmentioning

confidence: 90%

“…21,22 In that study, 1106 treatment-naive patients with CML-CP were randomized to receive either imatinib 400 mg daily or IFN plus cytarabine (n ¼ 553 patients each). 22 At 18 months, an MCyR was achieved in 87% of patients who received imatinib compared with 35% of patients who received IFN (P < .001).…”

Section: Imatinibmentioning

confidence: 99%

“…29 The safety, response, and survival advantages of imatinib over IFN has led to broad acceptance of imatinib as the drug of choice for initial therapy of CML. [21][22][23] Assessing imatinib response and resistance…”

Section: Imatinib Nilotinib Dasatinibmentioning

confidence: 99%

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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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“…3). 21 The MMR rate was higher in patients who achieved a CCyR (57% for imatinib vs 24% for IFN; P ¼ .003). After 6 years of imatinib therapy, long-term response rates remained high.…”

Section: Imatinib Nilotinib Dasatinibmentioning

confidence: 90%

Section: Imatinibmentioning

confidence: 99%

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Optimizing therapy for patients with chronic myelogenous leukemia in chronic phase

Kantarjian

Cortés

Rosée

et al. 2010

Cancer

Self Cite

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“…The development of the BCR/ABL tyrosine kinase inhibitor imatinib mesylate (Gleevec; formerly STI571) as the treatment of choice for chronic phase CML and its remarkable therapeutic effects suggest that blast crisis transition will be postponed for several years in the majority of CML patients (Deininger et al, 2005a;Roy et al, 2006). However, the persistence of BCR/ABL transcripts in a cohort of patients with complete cytogenetic response (Hughes et al, 2003) and the resistance of the primitive CML stem cell to imatinib treatment (Copland et al, 2006) raises the possibility that treatment with imatinib alone might delay but not prevent disease progression. Furthermore, most of the CML patients in the accelerated and blastic phases of the disease are either refractory or develop resistance to imatinib monotherapy (Deininger 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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“…It is indicated in all the patients who are in CP and are resistant to two TKIs. 10,11,28 What is the goal of treatment? The goal of treatment is dual: first, to ensure a normal survival; and second, to eradicate the leukemic cell clone, or to control the leukemic stem cell clone to an extent that treatment can be discontinued without relapse.…”

Section: Is There a Place For Tki-based Combinations?mentioning

confidence: 99%

Initial treatment for patients with chronic myeloid leukemia

Baccarani

2012

Leukemia Suppl

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The first-line treatment of chronic myeloid leukemia is based on the three currently available tyrosine kinase inhibitors (TKIs), namely imatinib, nilotinib and dasatinib. Nilotinib and dasatinib are more potent, and it is predicted that, in comparison with imatinib, they can reduce the risk of progression and increase the number of the patients who can discontinue the treatment without relapsing. Other TKIs are still being developed and may help to improve treatment options further on. Hydroxyurea has no longer a role. Allogeneic stem cell transplantation is the treatment of choice for the advanced phases, and in case of resistance to at least two TKIs.Leukemia Supplements (2012) 1, S37--S39; doi:10.1038/leusup.2012.21Keywords: chronic myeloid leukemia; BCR-ABL; Philadelphia chromosome; imatinib; nilotinib; dasatinib The initial treatment of Philadelphia-positive (Ph þ ), BCR-ABL þ chronic myeloid leukemia (CML) is based on tyrosine kinase inhibitors (TKI), a class of small molecules that can inhibit the phosphorylative function of the proteins that are coded by the BCR-ABL fusion gene on chromosome 22q. 1--4 These proteins are located in the cytoplasm, where they activate a number of downstream signals of proliferation and survival, resulting in the transformation of normal hematopoietic stem cells to leukemic cells. The Ph þ leukemic stem and progenitor cells on one hand proliferate and mature, expanding the myeloid tissue in the bone marrow and in the spleen, and causing leukocytosis, whereas on the other hand, they are genetically unstable and develop a number of secondary genomic lesions, leading to the progression from chronic to accelerated and blastic phase. 1--4 Therefore, the first goal of treatment is to prevent progression, and the second one is to eliminate the leukemic clone. Achieving the first goal may be sufficient to ensure a normal survival. Achieving the second goal may be necessary to cure the disease and discontinue the treatment safely. Both goals can be achieved with TKIs, although achieving the second goal may require other agents. TYROSINE KINASE INHIBITORSThe TKIs are a class of small molecules that have been designed with the purpose of inhibiting the phosphorylative activity of the TK. Several TKIs are able to inhibit the BCR-ABL proteins, although none is truly specific, because they inhibit other TKs as well. The TKIs that have been selected and registered so far for their activity on BCR-ABL, then for the treatment of CML, both first-line and second-line treatment, are as follows:Imatinib (Glivec or Gleevec, Novartis Pharma) 2,5 Nilotinib (Tasigna, Novartis Pharma) 2,6 Dasatinib (Sprycel, Bristol-Myers Squibb) 2,7 Another compound (Bosutinib, Pfizer) has already been tested in first-line and second-line treatment. 8 A fifth compound (Ponatinib, Ariad) has been tested in second-line and third-line treatment. 9 Imatinib, first of the class, was introduced more than 10 years ago. With imatinib, the complete hematologic response rate is close to 100%, the complete cytogenetic respon...

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Frequency of Major Molecular Responses to Imatinib or Interferon Alfa plus Cytarabine in Newly Diagnosed Chronic Myeloid Leukemia

Cited by 1,095 publications

References 35 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

Initial treatment for patients with chronic myeloid leukemia

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