Resistance Conferring Mutations

A number of BCR-ABL mutations have been identified that are associated with reduced sensitivity to TKI treatment in vitro.¹

Fortunately, clinical trials have shown that currently available BCR-ABL TKIs offer high rates of hematologic and cytogenetic responses in patients:

Exhibiting resistance due to most BCR-ABL mutations
Intolerant to their initial treatment. ^2,3

A notable exception is the mutation T315I, which can occur at the so-called "gateway" location-the ATP binding site within the P-loop. This mutation is associated with resistance to all of the currently available TKIs.¹ Patients who develop this mutation should be considered for stem cell transplantation or enrollment in a clinical trial.⁴

ABL protein with a tyrosine kinase inhibitor (TKI) blocking the ATP-binding site.

CML Therapy - BCR-ABL TKI Reduced Sensitivity

Call-outs show areas affected by common mutations associated with resistance to TKI treatment.^1,5

This research was originally published in Blood. Goldman JM. How I treat chronic
myeloid leukemia in the imatinib era. Blood. 2007;110:2828-2837. ® the
American Society of Hematology

Goldman JM. How I treat chronic myeloid leukemia in the imatinib era. Blood. 2007;110(8):2828-2837.
Kantarjian HM, Giles F, Gattermann N, et al. Nilotinib (formerly AMN107), a highly selective BCR-ABL tyrosine kinase inhibitor, is effective in patients with Philadelphia chromosome positive chronic myelogenous leukemia in chronic phase following imatinib resistance and intolerance. Blood. 2007;110(10):3540-3546.
Hochhaus A, Baccarani M, Deininger M, et al. Dasatinib induces durable cytogenetic responses in patients with chronic myelogenous leukemia in chronic phase with resistance or intolerance to imatinib. Leukemia. 2008;22(6):1200-1206.
National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology: Chronic Myelogenous Leukemia v.1.2009. http://www.nccn.org/professionals/physician_gls? PDF/cml/pdf. Accessed September 30, 2008.
Deininger M, Buchdunger E, Druker BJ. The development of imatinib as a therapeutic agent for chronic myeloid leukemia. Blood. 2005;105(7):2640-2653.