Nilotinib Superior to Imatinib as First-line for CML
Nilotinib Superior to Imatinib as First-line for CML
Nilotinib (Tasigna®) is a more potent BCR–ABL inhibitor than imatinib and was designed to overcome imatinib's deficiencies. Nilotinib has significant efficacy in patients with chronic myeloid leukemia (CML) in chronic phase, accelerated phase and blastic phase, following imatinib failure. Based on the results of the Evaluating Nilotinib Efficacy and Safety in Clinical Trials – Newly Diagnosed Patients (ENESTnd) study, the US FDA has granted accelerated approval of nilotinib for the treatment of adult patients with newly diagnosed Philadelphia chromosome-positive CML in chronic phase. Imatinib has changed our perceptions of the therapeutic power of targeted inhibition of a pathologically active kinase. Nilotinib, a designer agent built on the imatinib scaffold, has proven superior to its template agent by every significant surrogate marker we use in monitoring CML. Nilotinib's clinical superiority over imatinib, as demonstrated by the ENESTnd study, has established it as an agent that we believe is a significant further step towards the cure of CML.
Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder initially characterized by the presence of the Philadelphia chromosome (Ph), which is the result of a balanced reciprocal translocation involving the long arms of chromosomes 9 and 22. The fusion gene that is created by this translocation (Bcr–abl1) encodes for a constitutively active protein tyrosine kinase (breakpoint cluster region [BCR]– V-abl Abelson murine leukemia viral oncogene homolog 1 [ABL1]) that is primarily responsible for the leukemic phenotype. CML occurs in all age groups, but most commonly in the middle-aged and elderly, with a median age at diagnosis of 66 years in Western populations. Its annual incidence is 1–2 per 100,000 people, and slightly more men than women are affected. The only well-described risk factor for CML is exposure to ionizing radiation. Based on the National Cancer Institute Surveillance and Epidemiology End Results (SEER) database, we would anticipate that approximately 5000 new cases of CML will be diagnosed in the USA in 2010. Prior to the introduction of imatinib therapy, CML in chronic phase (CP) was usually followed by an accelerated phase (AP) and finally a terminal blastic phase (BP), which resembled either acute myeloid or acute lymphoblastic leukemia. This sequence has become somewhat less predictable with the introduction of imatinib therapy, with patients in essence being either in CP or having progressed (AP/BP). The prognosis of patients with CML improved dramatically in the late 1990s following the introduction of imatinib mesylate (Gleevec® [Novartis Pharmaceuticals, Basel, Switzerland], Glivec® [Novartis Pharmaceuticals]), a first in-class novel and somewhat selective inhibitor of BCR–ABL1. In newly diagnosed patients with CML, imatinib is inducing high complete hematologic and complete cytogenetic response rates (CCyR), low rates of progression to AP/BP of 7–10%, predominantly in the first 3 years of imatinib therapy, and an estimated 5-year survival rate of approximately 90%. The development of imatinib represents one of the most significant advances thus far achieved in the field of anticancer therapy. While the introduction of imatinib revolutionized the management of CML, a minority of patients remained who had primary or secondary resistance to treatment. Based on crystallographic studies, it was suggested that the potency and selectivity of imatinib could be improved by incorporating alternative binding groups to the N-methylpiperazine moiety of the compound. This led to the development of nilotinib (N-[3-[3-(1H-imadazolyl)propoxy] phenyl]-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino] benzamide), a high affinity aminopyrimidine-based ATP competitive BCR–ABL1 inhibitor (Box 1).
Abstract and Introduction
Abstract
Nilotinib (Tasigna®) is a more potent BCR–ABL inhibitor than imatinib and was designed to overcome imatinib's deficiencies. Nilotinib has significant efficacy in patients with chronic myeloid leukemia (CML) in chronic phase, accelerated phase and blastic phase, following imatinib failure. Based on the results of the Evaluating Nilotinib Efficacy and Safety in Clinical Trials – Newly Diagnosed Patients (ENESTnd) study, the US FDA has granted accelerated approval of nilotinib for the treatment of adult patients with newly diagnosed Philadelphia chromosome-positive CML in chronic phase. Imatinib has changed our perceptions of the therapeutic power of targeted inhibition of a pathologically active kinase. Nilotinib, a designer agent built on the imatinib scaffold, has proven superior to its template agent by every significant surrogate marker we use in monitoring CML. Nilotinib's clinical superiority over imatinib, as demonstrated by the ENESTnd study, has established it as an agent that we believe is a significant further step towards the cure of CML.
Introduction
Chronic myeloid leukemia (CML) is a clonal myeloproliferative disorder initially characterized by the presence of the Philadelphia chromosome (Ph), which is the result of a balanced reciprocal translocation involving the long arms of chromosomes 9 and 22. The fusion gene that is created by this translocation (Bcr–abl1) encodes for a constitutively active protein tyrosine kinase (breakpoint cluster region [BCR]– V-abl Abelson murine leukemia viral oncogene homolog 1 [ABL1]) that is primarily responsible for the leukemic phenotype. CML occurs in all age groups, but most commonly in the middle-aged and elderly, with a median age at diagnosis of 66 years in Western populations. Its annual incidence is 1–2 per 100,000 people, and slightly more men than women are affected. The only well-described risk factor for CML is exposure to ionizing radiation. Based on the National Cancer Institute Surveillance and Epidemiology End Results (SEER) database, we would anticipate that approximately 5000 new cases of CML will be diagnosed in the USA in 2010. Prior to the introduction of imatinib therapy, CML in chronic phase (CP) was usually followed by an accelerated phase (AP) and finally a terminal blastic phase (BP), which resembled either acute myeloid or acute lymphoblastic leukemia. This sequence has become somewhat less predictable with the introduction of imatinib therapy, with patients in essence being either in CP or having progressed (AP/BP). The prognosis of patients with CML improved dramatically in the late 1990s following the introduction of imatinib mesylate (Gleevec® [Novartis Pharmaceuticals, Basel, Switzerland], Glivec® [Novartis Pharmaceuticals]), a first in-class novel and somewhat selective inhibitor of BCR–ABL1. In newly diagnosed patients with CML, imatinib is inducing high complete hematologic and complete cytogenetic response rates (CCyR), low rates of progression to AP/BP of 7–10%, predominantly in the first 3 years of imatinib therapy, and an estimated 5-year survival rate of approximately 90%. The development of imatinib represents one of the most significant advances thus far achieved in the field of anticancer therapy. While the introduction of imatinib revolutionized the management of CML, a minority of patients remained who had primary or secondary resistance to treatment. Based on crystallographic studies, it was suggested that the potency and selectivity of imatinib could be improved by incorporating alternative binding groups to the N-methylpiperazine moiety of the compound. This led to the development of nilotinib (N-[3-[3-(1H-imadazolyl)propoxy] phenyl]-4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino] benzamide), a high affinity aminopyrimidine-based ATP competitive BCR–ABL1 inhibitor (Box 1).
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