The evolving role of mutational testing

The use of mutational testing is evolving in clinical practice as additional research becomes available to provide appropriate direction on how to best utilize this tool.

Testing at baseline

Current guidelines and available data do not support routine mutational testing for most patients¹
There is no established role for mutational testing in chronic-phase patients at baseline/prior to therapy, or in patients responding to initial therapy¹

Testing in patients with evidence of treatment resistance

In the absence of head-to-head comparative studies and definitive data linking common mutations to treatment response, the choice of alternative BCR-ABL TKI treatment should be based on clinical considerations, such as the safety, tolerability, and efficacy of each agent as well as patient comorbidities.^2,3

In treatment-resistant patients, mutational testing results may be useful to identify T315I and a small number of uncommon mutations showing lower response rates for alternate TKIs.¹

Mutations That Have Been Identified in Patients
with Treatment-Resistant CML

Location

Approximate
frequency

Impact on sensitivity
to TKIs in vitro

T315I

2%^4-7

Resistance to all currently available TKIs

G250E E255K/V H396R M244V Y253H Q252H F359C/V

7% - 10%^6,7 2% - 7%^6-8 3% - 6%^6,7 2% - 4%^6,7 2%⁷ 2%^6,7 1% - 2%^6-8

Loss of
sensitivity
to at least
1 TKI

Impact of mutations other than T315I

With the exception of the T315I mutation, there is insufficient evidence to support choosing second-line treatment based on mutational testing. Clinical trials of BCR-ABL TKIs in treatment-experienced patients have shown that response rates are similar in patients with and without BCR-ABL mutations at baseline.^5,7-9

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.
Schiffer CA. BCR-ABL tyrosine kinase inhibitors for chronic myelogenous leukemia. N Engl J Med. 2007;357(3):258-265.
Apperley JF. Part II: management of resistance to imatinib in chronic myeloid leukaemia. Lancet Oncol. 2007;8(12):1116-1128.
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.
Kantarjian H, Giles F, Wunderle L, et al. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. N Engl J Med. 2006;354(24):2542-51.
Kantarjian H, Giles F, Wunderle L, et al. Nilotinib in imatinib-resistant CML and Philadelphia chromosome-positive ALL. Supplementary appendix. www. http://content.nejm.org/cgi/content/full/354/24/ 2542/DC1.
Hochhaaus A, Kantarjian HM, Baccarani M, et al. Dasatinib induces notable hematologic and cytogenetic responses in chronic-phase chronic myeloid leukemia after failure of imatinib therapy. Blood. 2007;109(6):2303-2309.
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. Dasatinib for the treatment of Philadelphia chromosome-positive chronic myelogenous leukaemia after imatinib failure. Expert Opin Pharmacother. 2007: 8(18):3257-3264.