Status of Therapy for Chronic Myeloid Leukemia: Review of Drug Development
Status of Therapy for Chronic Myeloid Leukemia: Review of Drug Development
Chronic myeloid leukemia (CML) has led the way for developing rational drug development in cancer. Most cases of CML diagnosed and treated in chronic phase are extremely well controlled with imatinib monotherapy, and primary resistance is very uncommon. Even though the treatment failure rate is low, the emergence of drug resistance and the lack of eradication of the hematopoietic stem cell clone has prompted a wave of drugs to address one or both these problems. Several clinical trials (Phase I and II) of dasatinib or nilotinib in the treatment of imatinib-resistant or -intolerant Ph chromosome-positive leukemia have already reported a remarkable rate of hematologic response greater than 90% for chronic-phase patients. These drugs minimize the risk of acquired drug resistance that is particularly seen within the first 24-36 months of therapy, and can prevent early failure in these patients, Furthermore, rational, noncross-resistant combinations that include a T315I inhibitor and drugs that can eradicate the hematopoietic stem cell clone may extend the coverage to virtually all patients with bcr-abl. Here we review the 6-year impact of the 'magic pill', Gleevec, (Glivec), including the emerging problems with its treatment, the efficacy data of dasatinib and nilotinib and the very promising data of the newer generation of drugs for CML.
Chronic myeloid leukemia (CML) is a myeloproliferative disorder that can occur in a bi- or tri-phasic course. CML occurs with an incidence of approximately 1-1.5 cases per 100,000 population, and accounts for approximately 7-15% of newly diagnosed cases of leukemia in adults. As per the NCI's Surveillance, Epidemiology, and End Results (SEER) Cancer Statistics Review, it is estimated that 4830 men and women (2800 men and 2030 women) will be diagnosed with CML, and 450 men and women will die from the disease in 2008. The median age at presentation is around 66 years. In the preimatinib era, the median survival was 4-6 years (range <1 year to >10 years). Survival after the development of an accelerated phase is usually less than 1 year and only a few months after blastic transformation.
The typical course of disease is characterized by an initial chronic phase lasting for 3-6 years, followed by an accelerated, then blastic phase usually of short duration. A total of 75-80% of patients go through an accelerated phase before the blastic phase. The definition for accelerated phase is not uniform, which needs to be verified when evaluating treatments. Specific criteria associated with a survival shorter than 18 months by multivariate analysis have been proposed, including the presence of ≥15% blasts, or ≥30% blasts and promyelocytes, or ≥20% basophils in blood or platelet count <100. A cytogenetic clonal evolution is also considered criteria for acceleration. Recent analysis suggests its prognostic effect depends on the specific abnormality, its predominance in marrow metaphases and the time of appearance.
The cytogenetic hallmark of CML is a reciprocal t(9,22)(q34;q11) chromosomal translocation that creates a derivative 9q+ and a small 22q-, known as the Ph chromosome. The latter harbors the bcr-abl fusion gene encoding the chimeric bcr-abl protein with a deregulated tyrosine kinase activity, the expression of which has been shown to be necessary and sufficient for the transformed phenotype of CML cells. The activation of multiple signal transduction pathways in bcr-abl transformed cells leads to increased proliferation, reduced growth-factor dependence and apoptosis, and perturbed interaction with the extracellular matrix and stroma. CML is a quintessential example in human neoplasia, wherein a single oncogenic fusion abnormality plays a central role in its pathology.
Chronic myeloid leukemia (CML) has led the way for developing rational drug development in cancer. Most cases of CML diagnosed and treated in chronic phase are extremely well controlled with imatinib monotherapy, and primary resistance is very uncommon. Even though the treatment failure rate is low, the emergence of drug resistance and the lack of eradication of the hematopoietic stem cell clone has prompted a wave of drugs to address one or both these problems. Several clinical trials (Phase I and II) of dasatinib or nilotinib in the treatment of imatinib-resistant or -intolerant Ph chromosome-positive leukemia have already reported a remarkable rate of hematologic response greater than 90% for chronic-phase patients. These drugs minimize the risk of acquired drug resistance that is particularly seen within the first 24-36 months of therapy, and can prevent early failure in these patients, Furthermore, rational, noncross-resistant combinations that include a T315I inhibitor and drugs that can eradicate the hematopoietic stem cell clone may extend the coverage to virtually all patients with bcr-abl. Here we review the 6-year impact of the 'magic pill', Gleevec, (Glivec), including the emerging problems with its treatment, the efficacy data of dasatinib and nilotinib and the very promising data of the newer generation of drugs for CML.
Chronic myeloid leukemia (CML) is a myeloproliferative disorder that can occur in a bi- or tri-phasic course. CML occurs with an incidence of approximately 1-1.5 cases per 100,000 population, and accounts for approximately 7-15% of newly diagnosed cases of leukemia in adults. As per the NCI's Surveillance, Epidemiology, and End Results (SEER) Cancer Statistics Review, it is estimated that 4830 men and women (2800 men and 2030 women) will be diagnosed with CML, and 450 men and women will die from the disease in 2008. The median age at presentation is around 66 years. In the preimatinib era, the median survival was 4-6 years (range <1 year to >10 years). Survival after the development of an accelerated phase is usually less than 1 year and only a few months after blastic transformation.
The typical course of disease is characterized by an initial chronic phase lasting for 3-6 years, followed by an accelerated, then blastic phase usually of short duration. A total of 75-80% of patients go through an accelerated phase before the blastic phase. The definition for accelerated phase is not uniform, which needs to be verified when evaluating treatments. Specific criteria associated with a survival shorter than 18 months by multivariate analysis have been proposed, including the presence of ≥15% blasts, or ≥30% blasts and promyelocytes, or ≥20% basophils in blood or platelet count <100. A cytogenetic clonal evolution is also considered criteria for acceleration. Recent analysis suggests its prognostic effect depends on the specific abnormality, its predominance in marrow metaphases and the time of appearance.
The cytogenetic hallmark of CML is a reciprocal t(9,22)(q34;q11) chromosomal translocation that creates a derivative 9q+ and a small 22q-, known as the Ph chromosome. The latter harbors the bcr-abl fusion gene encoding the chimeric bcr-abl protein with a deregulated tyrosine kinase activity, the expression of which has been shown to be necessary and sufficient for the transformed phenotype of CML cells. The activation of multiple signal transduction pathways in bcr-abl transformed cells leads to increased proliferation, reduced growth-factor dependence and apoptosis, and perturbed interaction with the extracellular matrix and stroma. CML is a quintessential example in human neoplasia, wherein a single oncogenic fusion abnormality plays a central role in its pathology.