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How I Manage: Chronic Myeloid Leukemia by Jerald Radich, MD

" The tyrosine kinase inhibitors (TKIs) have irrevocably changed the care of chronic myeloid leukemia (CML) patients, dramatically changing the natural history of this disease.1-4 With multiple TKIs available, we now have an “embarrassment of riches” in treatment options. Below are some common questions and clinically relevant answers regarding treatment.

The choices are imatinib (Gleevec, Novartis) and the more potent second-generation TKIs nilotinib (Tasigna, Novartis) and dasatinib (Sprycel, Bristol-Myers Squibb). Here are some basic considerations for selecting therapy:........"

Targeting of the MNK–eIF4E axis in blast crisis CML inhibits leukemia stem cell function


Cancer stem cells (CSCs) frequently acquire the ability to self-renew and persist in their hosts by coopting normal stem cell programs. Blast crisis (BC) chronic myeloid leukemia is a prototypic example, as the acquired activation of β-catenin signaling that enables BC CSC function is also important in normal hematopoietic stem cell maintenance. In identifying eIF4E phosphorylation by the MNK kinases as a necessary step in β-catenin activation in BC CSCs, but not normal hematopoietic stem cells, we define a therapeutic target in BC. Our studies suggest that clinical trials with MNK kinase inhibitors are warranted in BC chronic myeloid leukemia.

read Abstract here

population study shows the advent of 2ndGen TKIs has improved progression-free survival in CML

Sebastian Francis, Claire Lucas, Steven Lane, Lihui Wang, Sarah Watmough, Katy Knight, Jo Bell, Mohammed Kaleel-Rahman, Edwin Lee, David O’Brien, Nauman M. Butt, Walid Sadik, Lally De Soysa, Jim R.C. Seale, Rahuman Salim, Richard E. Clark
Received 30 October 2012; published online 24 April 2013.

Population based data suggest the proportion of patients failing imatinib in chronic myeloid leukaemia (CML) is higher than the reported one-third of patients in clinical trials. Clinical trials have demonstrated second generation tyrosine kinase inhibitors (TKI) dasatinib and nilotinib can restore complete cytogenetic remission (CCR) and major molecular response (MMR) to many patients failing imatinib, but their impact in the general population is not clear.

Design and methods
We report CML outcome in a population of 2.3 million people in a geographically contiguous area of North West England and North Wales.

Between 2003 and 2009, 192 new CML cases were diagnosed, of whom 184 were in chronic phase and 160 started on imatinib. The maximal CCR rate was 65% at 24 months and the maximal MMR rate was 50% at 36 months. Patients diagnosed since second generation TKI became available for imatinib failure had a more rapid cumulative CCR and MMR rate and a significantly improved progression free survival (p=0.022) than those diagnosed before this time.

The study indicates that second generation TKI have improved CML outcome in the general population.


Early molecular response and female sex strongly predict stable undetectable BCR-ABL1, the criteria for imatinib discontinuation in patients with CML

Susan Branford1,2,3, David T. Yeung1,2,4, David M. Ross2,4,5, Jodi A. Prime1, Chani R. Field1, Haley K. Altamura1, Alexandra L. Yeoman1, Jasmina Georgievski1, Bronte A. Jamison1, Stuart Phillis1, Brad Sullivan1, Nancy E. Briggs6, Mark Hertzberg7,8, John F. Seymour7,9, John Reynolds10, and Timothy P. Hughes2,4,7
+ Author Affiliations

Key Points

1. Independent predictors of stable, undetectable BCR-ABL1 during first-line imatinib therapy were female sex and the BCR-ABL1 value at 3 months.

2. Time to achieve an MMR influenced time to stable, undetectable BCR-ABL1, suggesting slower dynamics of BCR-ABL1 decline with delayed MMR.

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Dynamics of chronic myeloid leukemia response to long-term targeted therapy reveal treatment effects on leukemic stem cells

Min Tang1, Mithat Gonen2, Alfonso Quintas-Cardama3, Jorge Cortes3, Hagop Kantarjian3, Chani Field4, Timothy P. Hughes4, Susan Branford4, and Franziska Michor1

+ Author Affiliations
1Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, and Department of Biostatistics, Harvard School of Public Health, Boston, MA;2Department of Biostatistics and Epidemiology, Memorial Sloan-Kettering Cancer Center, New York, NY;3Department of Leukemia, University of Texas M. D. Anderson Cancer Center, Houston, TX; and4Department of Genetics and Molecular Pathology, SA Pathology, and University of Adelaide, Adelaide, Australia

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Price of drugs for chronic myeloid leukemia (CML), reflection of the unsustainable cancer drug prices: perspective of CML Experts

Blood First Edition Paper, prepublished online April 25, 2013; DOI 10.1182/blood-2013-03-490003

As a group of more than 100 experts in chronic myeloid leukemia (CML),
we draw attention to the high prices of cancer drugs, with the particular
focus on the prices of approved tyrosine kinase inhibitors for the treatment
of CML. This editorial addresses the multiple factors involved in cancer
drug pricing, their impact on individual patients and healthcare policies, and
argues for the need to lower the prices of cancer drugs to allow more
patients to afford them and to maintain sound long-term healthcare policies.

ESK1-New Monoclonal Antibody Targets Intracellular Oncogenic Proteins in Leukemias

Michael Kaufman | March 26, 2013

'While WT1 is overexpressed in leukemias and other cancers, including myeloma, and breast, ovarian, and colorectal cancers, it is found in few healthy cells, which makes side effects less likely to occur from drugs that target it. “This is a new approach for attacking WT1, an important cancer target, with an antibody therapy,” said lead author David A. Scheinberg, MD, PhD, chair of the Sloan-Kettering Institute's molecular pharmacology and chemistry program and an inventor of the antibody. “This is something that was previously not possible. There has not been a way to make small-molecule drugs that can inhibit WT1 function. Our research shows that you can use a monoclonal antibody to recognize a cancer-associated protein inside a cell, and it will destroy the cell.”
In the current study, “ESK1 bound to several leukemia and solid tumor cell lines and primary leukemia cells,” wrote the authors. “Low doses of naked ESK1 antibody cleared established, disseminated, human acute lymphocytic leukemia and Philadelphia chromosome–positive leukemia in nonobese diabetic/severe combined immunodeficient γc−/− (NSG) mouse models. At therapeutic doses, no toxicity was seen in HLA-A0201 transgenic mice.”
“We were surprised that the antibody worked so well on its own,” said Scheinberg. “We had originally expected that we might need to use the antibody as a carrier to deliver a drug or a radioactive therapy to kill the cancer cells, but this was not necessary.”...'

Full article here:

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:


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 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:

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:

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