Which TKI Should Be Recommended as Initial Treatment for CML in Chronic Phase?

Schiffer, MD1 | October 12, 2012

Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan

The lessons learned from the specifically ”targeted” treatment of patients with chronic myeloid leukemia (CML) using imatinib(Drug information on imatinib) (Gleevec) are now being applied with sometimes dramatic success in a variety of other tumors in which critical driving mutations have been identified, including some, such as malignant melanoma and lung cancer, that are notoriously resistant to other treatments. Sadly, but as might have been predicted from the experience in more advanced-stage CML, resistance due to new mutations in the genes coding for the targeted proteins, as well as to changes in other signaling pathways, often develops, and newer drugs and perhaps combination approaches may be needed.
The overall results with tyrosine kinase inhibitors (TKIs) in CML in chronic phase remain excellent, however, and Drs. Goldman and Marin nicely summarize the results of current treatments and the dilemmas posed by the availability of three (and perhaps soon four) alternatives to imatinib—although they do not actually tell us what they would recommend to the next newly diagnosed patient whom they will see in their practice. Some points of reference for my further discussion:

Full article here:
http://www.cancernetwork.com/chronic-myeloid-leukemia/content/article/10...

---------------------------------------------------------------------------------------------------------------------------

Is Imatinib Still an Acceptable First-Line Treatment for CML in Chronic Phase?
Challenging Situations in the Management of Leukemias
By John M. Goldman, DM, FRCP, FRCPath, FMedSci1, David Marin, MD, FRCP1
October 12, 2012
1Imperial College London, United Kingdom

ABSTRACT: The introduction of the tyrosine kinase inhibitor (TKI) imatinib(Drug information on imatinib) (Gleevec) into clinical practice resulted in a very dramatic prolongation of survival for most, but not all, patients with chronic myeloid leukemia in chronic phase (CML-CP). A leukemia with a median survival of about 5 years was transformed into one for which the survival in many cases promises to be comparable to that of normal persons of similar age. The more recently available TKIs, namely nilotinib(Drug information on nilotinib) (Tasigna) and dasatinib(Drug information on dasatinib) (Sprycel), produce more rapid responses but have not yet shown any overall survival advantage compared with long-term administration of imatinib. They are, however, useful in treating imatinib intolerance or resistance. There are currently two choices for initial treatment of CML-CP: (1) starting all new patients on imatinib and changing to a second-generation TKI in those who fail or who are predicted to fare badly, or (2) starting all new patients on a second-generation TKI. This choice may be based primarily on considerations of cost or possible side effects.

Full article here@
http://www.cancernetwork.com/chronic-myeloid-leukemia/content/article/10...

----------------------------------------------------------------------------------------------------------------------------------------

Front-Line TKI Therapy for Chronic-Phase CML: the Luxury of Choice
By Neil P. Shah, MD, PhD1 | October 12, 2012
1 Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco

The modern era of targeted tyrosine kinase inhibitor (TKI) therapy for the treatment of human malignancies was ushered in by the BCR-ABL TKI imatinib(Drug information on imatinib) (Gleevec) in glorious fashion by Brian Druker and colleagues.[1] Upon its approval in 2001, imatinib was rapidly adopted (despite an absence of long-term outcome and safety data) as first-line therapy for newly diagnosed chronic myeloid leukemia (CML) patients in chronic phase—even for younger patients who were excellent candidates for the established curative procedure of allogeneic stem-cell transplantation. The enthusiasm for imatinib was largely based on its ease of administration, its good tolerability (particularly relative to interferon), and most notably, its efficacy. Complete cytogenetic response (CCyR), which had previously been recognized as a surrogate marker of progression-free and overall survival—and which remains a critical goal of treatment today—was achieved in the majority of patients treated with imatinib.[2] Longer-term follow-up has provided firm justification for the initial optimism regarding imatinib in cases of chronic phase CML. With 8 years of follow-up, it appears that the likelihood of dying of CML is approximately equivalent to the likelihood of dying of other causes,[3] and it is hoped that with longer follow-up and more access to effective next-generation TKIs, the majority of chronic-phase CML patients, in stark contrast to historical experience, will die of causes unrelated to CML or its treatment.
However, longer follow-up has also shown that a substantial proportion of patients discontinue imatinib because of treatment failure or toxicity.[3] It is important to note that definitions of imatinib failure have evolved as clinical trial data have matured, and many patients who continued imatinib in the landmark International Randomized Study of Interferon and STI571 (IRIS study) would have been removed relatively early for treatment failure had treatment milestones that incorporate a current understanding of imatinib failure been employed at the time. For instance, approximately 25% of patients treated with front-line imatinib fail to achieve CCyR by 18 months,[4] a widely accepted (and perhaps conservative) definition of treatment failure......

Full article here:
http://www.cancernetwork.com/chronic-myeloid-leukemia/content/article/10...