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PH+ CML Information
Ph+ CML: Resistance
The vast majority of newly diagnosed adult patients with Ph+ CML in chronic phase treated with imatinib mesylate achieve a complete hematological response and a complete cytogenetic response. However, a percentage of patients across all phases of disease either fail to achieve an adequate response to imatinib mesylate or lose their response over time.1
The mechanisms responsible for the rare cases of primary resistance—failure to achieve a defined level of response—are still being investigated. However, the mechanisms of secondary resistance—an increase in disease activity after a response at the hematologic, cytogenetic, or molecular level—are largely understood.1
Bcr-Abl remains the key
Reactivation of Bcr-Abl signaling is the most common cause of acquired resistance to imatinib mesylate, which suggests that targeting Bcr-Abl remains the most appropriate Ph+ CML treatment strategy.1 Several mechanisms responsible for resistance have been identified:
- Mutations in the kinase domain of Bcr-Abl that impair drug binding1
- BCR-ABL gene amplification, potentially leading to overproduction of Bcr-Abl protein1
- Increased expression of BCR-ABL mRNA2
Identifying Resistance in Patients
Clinicians can identify patients who may be resistant to treatment. Specifically, resistance can be tied to the following treatment milestones and timepoints:3
- Failure to achieve a CHR at 3 months
- Failure to achieve a CyR ( < 95% Ph+ cells) at 6 months
- Failure to achieve a MCyR ( < 35% Ph+ cells) at 12 months
- Disease progression at any time after a previous HR or CyR
Patients who fit any of the above criteria should be considered for treatment with Tasigna®.
Continued Monitoring Essential
Researchers have detected mutations associated with imatinib mesylate resistance in samples from patients taken prior to imatinib mesylate therapy.4 This suggests that mutational cells are selected in the presence of imatinib mesylate, much like the proliferation of drug-resistant bacteria under the selective pressure of antibiotics.2 Even among patients who achieve a 3-log reduction in leukemic burden, few achieve undetectable levels of Bcr-Abl transcripts.5 Ongoing molecular monitoring of minimal residual disease using quantitative PCR, even in good responders, may help with disease management.6
Fig. 3. Baccarani M, Saglio G, Goldman J, et al. Evolving concepts in the management of chronic myeloid leukemia. Recommendations from an expert panel on behalf of the European LeukemiaNet. Blood. 2006;108:1809-1820.
1. Shah, Neil. "Loss of Response to Imatinib: Mechanics and Management." Hematology. 2005: 183-87.
2. Deininger, Michael. "Resistance to Imatinib: Mechanisms and Management." Journal of the National Comprehensive Cancer Network. 2005;6: 757-68.
3. Kantarjian H, Giles F, Wunderle L, et al. "Nilotinib in Imatinib-Resistant CML and Philadelphia Chromosome–Positive ALL." N Engl J Med. 2006;354: 2542-51.
4. Roche-Lestienne, Catherine. "Several Types of Mutations of the Abl Gene Can Be Found in Chronic Myeloid Leukemia Patients Resistant to Sti571, and They Can Pre-Exist to the Onset of Treatment." Blood. 2002;100: 1014-18.
5. O'Hare, Thomas. "Amn107: Tightening the Grip of Imatinib." Cancer Cell. 2005;7: 117-19.
6. Hughes T, Branford S. "Molecular Monitoring of Bcr–Abl as a Guide to Clinical Management in Chronic Myeloid Leukemia." Blood. 2006; 20: 29-41.
