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

Charles A. 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...

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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 ...read more

Nilotinib for CML Leads to Fewer Treatment-Emergent Mutations Than Imatinib

Dave Levitan | April 12, 2013

Chronic myeloid leukemia (CML) patients treated with nilotinib(Drug information on nilotinib) had fewer treatment-emergent BCR-ABL mutations than those treated with imatinib(Drug information on imatinib), and among patients who did have a mutation, those treated with nilotinib had reduced rates of progression to accelerated phase and blast phase of the disease, according to results from the phase III ENESTnd trial.
Ball-and-stick model of nilotinib
“Mutations in the kinase domain of BCR-ABL are a common mechanism of resistance to TKI therapy, and these mutations have been detected in 40% to 60% of imatinib-resistant patients,” wrote study authors led by Andreas Hochhaus, MD, of the University Medical Center Jena in Germany, in the journal Blood, on March 15. Researchers have previously identified more than 90 distinct mutations, and nilotinib has in vitro inhibitory activity against all but one of these.

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

Chronic Fatigue Limits Quality of Life in Imatinib-Treated CML Patients

Dave Levitan | April 16, 2013

A study of patients with chronic myeloid leukemia (CML) treated with imatinib found that chronic fatigue is the major factor that limits health-related quality of life (HRQOL).
Blast crisis of CML: Peripheral blood smear revealing the histopathologic features indicative of a blast crisis in the case of CML
HRQOL has become substantially more important in the treatment of CML, as 5-year survival rates have climbed dramatically with the use of tyrosine kinase inhibitors, such as imatinib. Factors associated with HRQOL, though, have not been clearly studied. “Such information would have important clinical implications, for example, to lay the groundwork for developing targeted supportive care programs for CML survivors,” wrote study authors led by Fabio Efficace, PhD, of the Italian Group for Adult Hematologic Diseases in Rome. The new study was published online ahead of print on March 15 in Leukemia.

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

Long-Term Treatment With Imatinib Affected Bone Mineral Density

By Leah Lawrence | April 15, 2013

A majority of patients on imatinib(Drug information on imatinib) for treatment of gastrointestinal stromal tumor (GIST) or chronic myelogenous leukemia (CML) had low or absent levels of osteocalcin, a bone marker secreted by osteoblasts, and about 50% of patients had a decrease in bone mineral density, signaling that long-term treatment may affect bone health in these patients.
Chemical structure of imatinib
“We had previously published a paper in 2006 that showed that patients who take imatinib for CML or for GIST tumors have decreased activity for osteoblasts,” said Ellin Berman, MD, lead researcher on the study and a hematologist at Memorial Sloan-Kettering Cancer Center in New York. “We wanted to prospectively look at whether this had a clinical impact on patients.”

The results were published in Leukemia Research.... read full article here

http://www.cancernetwork.com/gastrointestinal-stromal-tumor/content/arti...

See article in Blood on this side effect of imatinib in a subgroup of patients

Dysregulation of bone remodeling by imatinib mesylate

Kate Vandyke1,2, Stephen Fitter1, Andrea L. Dewar1, Timothy P. Hughes2,3, and Andrew C. W. Zannettino1,2

'An additional common and unexpected side effect of imatinib therapy is disturbed calcium and phosphate metabolism, as evidenced by decreased serum phosphate and calcium levels. ...read more

Rapid mobilization of cytotoxic lymphocytes induced by dasatinib therapy

S Mustjoki1, K Auvinen2,10, A Kreutzman1,10, P Rousselot3, S Hernesniemi1, T Melo4, A-M Lahesmaa-Korpinen5, S Hautaniemi5, S Bouchet6, M Molimard6, R Smykla7, F Y Lee7, J Vakkila1, S Jalkanen2,8, M Salmi2,9 and K Porkka1

Abstract
Tyrosine kinase inhibitors (TKIs) have potent effects on malignant cells, and they also target kinases in normal cells, which may have therapeutic implications.
http://www.nature.com/leu/journal/v27/n4/abs/leu2012348a.html

Combining BCR-ABL1 transcript levels at 3 and 6 months in chronic myeloid leukemia: implications for early intervention strategies

Pratap Neelakantan1, Gareth Gerrard1, Claire Lucas2, Dragana Milojkovic1, Philippa May1, Lihui Wang2, Christos Paliompeis1, Marco Bua1, Alistair Reid1, Katayoun Rezvani1, Stephen O'Brien3, Richard Clark2, John Goldman1, and David Marin1,

Abstract
Several groups have shown that that the BCR-ABL1 transcript level measured at 3 or 6 months after starting treatment with tyrosine kinase inhibitors strongly predicts for clinical outcomes for CML patients. In this work we asked whether the prognostic value of the 3-month transcript level could be improved by combining the 3- and 6- month results.

http://bloodjournal.hematologylibrary.org/content/early/2013/02/04/blood...

Trying to Calculate the Economic Value of Dasatinib or Nilotinib for Imatinib-Resistant CML

Trying to Calculate the Economic Value of Dasatinib or Nilotinib for Imatinib-Resistant CML
Published Online: Thursday, March 28, 2013

Although it is now standard practice to utilize the second-generation tyrosine-kinase inhibitors dasatinib or nilotinib in patients whose chronic myeloid leukemia (CML) has recurred while taking imatinib treatment, published support for the economic value of this approach is lacking. Investigators from the University of Exeter, United Kingdom, conducted a review of the literature and produced an economic model to help fill this information gap.

http://www.onclive.com/publications/obtn/2013/March-2013/Trying-to-Calcu...

Occurrence and current management of side effects in chronic myeloid leukemia patients treated frontline with tyrosine kinase inhibitors

Occurrence and current management of side effects in chronic myeloid leukemia patients treated frontline with tyrosine kinase inhibitors
Massimo Breccia, Giuliana Alimena.

Department of Cellular Biotechnology and Hematology, Sapienza University, Rome, Italy.

1. Introduction ...read more

Nilotinib is associated with a reduced incidence of BCR-ABL mutations versus imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase

Nilotinib is associated with a reduced incidence of BCR-ABL mutations versus imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase
Andreas Hochhaus1, Giuseppe Saglio2, Richard A. Larson3, Dong-Wook Kim4, Gabriel Etienne5, Gianantonio Rosti6, Carmino De Souza7, Mineo Kurokawa8, Matt E. Kalaycio9, Albert Hoenekopp10, Xiaolin Fan11, Yaping Shou11, Hagop M. Kantarjian12, and Timothy P. Hughes13

Key points:
~ Frontline nilotinib led to fewer and less diverse BCR-ABL mutations than imatinib in patients with chronic myeloid leukemia in chronic phase
~ Rates of progression to accelerated phase/blast crisis were lower with nilotinib than imatinib in patients with emergent BCR-ABL mutations

http://bloodjournal.hematologylibrary.org/content/early/2013/03/15/blood...

EMA approves marketing authorisation for ponatinib/Iclusig

21 March 2013
EMA/CHMP/178415/2013 Committee for Medicinal Products for Human Use (CHMP)

Summary of opinion1 (initial authorisation)

Iclusig
Ponatinib

On 21 March 2013, the Committee for Medicinal Products for Human Use (CHMP) adopted a positive
opinion, recommending the granting of a marketing authorisation for the medicinal product Iclusig
15 mg and 45 mg film-coated tablets intended for the treatment of chronic myeloid leukaemia (CML)
and Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph+ ALL). Iclusig was
designated as an orphan medicinal product on 2 March 2010. The applicant for this medicinal product
is ARIAD Pharma Ltd.

http://www.ema.europa.eu/docs/en_GB/document_library/Summary_of_opinion_...

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