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State of CML Treatments

By Michael Mauro, MD1, Jerald Radich, MD2
July 25, 2013

1Memorial Sloan-Kettering Cancer Center, New York
2Fred Hutchinson Cancer Research Center, Seattle

Interviewed by Anna Azvolinsky, PhD

Chronic myeloid leukemia (CML) is now seen as a classic example of a malignancy driven by a mutation, the BCR-ABL fusion gene on the Philadelphia chromosome. This fusion gene produces a continuously active tyrosine kinase that is thought to drive CML. The first small molecule inhibitor against BCR-ABL approved by the US Food and Drug Administration (FDA) was imatinib(Drug information on imatinib), or Gleevec. There are now several newer BCR-ABL inhibitors that can treat CML patients resistant to this earlier targeted therapy. Today, we are speaking with Michael Mauro, MD, of the Memorial Sloan-Kettering Cancer Center in New York and formerly of the Knight Cancer Institute in Portland, Oregon, and Dr. Jerald Radich, of the Fred Hutchinson Cancer Research Center in Seattle.
Both Dr. Mauro and Dr. Radich are involved in clinical research into the genetics of CML and how to optimize care for these patients with CML.

CANCER NETWORK: Dr. Mauro, can you give a brief overview of how Philadelphia chromosome–associated CML typically develops and how imatinib changed the course of the disease?....................

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

EUTOS Score Validated for Predicting Treatment Outcomes With TKI Therapy

By Dave Levitan | July 12, 2013

While tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of chronic myeloid leukemia (CML) in recent years, prognosis of the disease and prediction of response to those treatments has fallen behind. A new study validates a simple prognostic score known as the EUTOS score, featuring only two variables, as a useful tool in prediction of therapeutic effects of TKIs, and especially of imatinib(Drug information on imatinib).
Before TKIs were developed, the Sokal risk score was developed and used for patients receiving conventional chemotherapy for CML. In the era of interferon-alfa treatment, the Euro risk score was established. But the rapid development and adoption of imatinib and other TKIs did not bring another score system with it, and the Sokal and Euro scores were still used.

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

'CML Horizons' 2013 Report

Read the report from the 11th International Conference for Organisations Representing People with CML.
Prague, Czech Republic. 3rd-5th May 2013.

Europe Approves Ponatinib as Orphan Drug for Leukemias -

Zosia Chustecka
Jul 02, 2013

The European Commission has granted marketing authorization to ponatinib (Iclusig, Ariad Pharmaceuticals) as an orphan drug for use in certain leukemia patients who have stopped responding to or cannot tolerate other therapies.

Specifically, ponatinib is indicated for use in adults with chronic myeloid leukemia (CML) in the chronic, accelerated, or blast phase who are resistant to dasatinib (Sprycel) or nilotinib (Tasigna), who are intolerant of dasatinib or nilotinib and for whom subsequent treatment with imatinib (Gleevec) is not clinically appropriate, or who have the T315I mutation.

In addition, it is indicated for adults with Philadelphia (Ph) chromosome-positive acute lymphoblastic leukemia (ALL) who are resistant to dasatinib, who are intolerant to dasatinib and for whom subsequent treatment with imatinib is not clinically appropriate, or who have the T315I mutation.

http://www.medscape.com/viewarticle/807207

European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013

Michele Baccarani1,*, Michael W. Deininger2, Gianantonio Rosti3, Andreas Hochhaus4, Simona Soverini3, Jane F. Apperley5, Francisco Cervantes6, Richard E. Clark7, Jorge E. Cortes8, François Guilhot9, Henrik Hjorth-Hansen10, Timothy P. Hughes11, Hagop M. Kantarjian8, Dong-Wook Kim12, Richard A. Larson13, Jeffrey H. Lipton14, François-Xavier Mahon15, Giovanni Martinelli3, Jiri Mayer16, Martin C. Müller17, Dietger Niederwieser18, Fabrizio Pane19, Jerald P. Radich20, Philippe Rousselot21, Giuseppe Saglio22, Susanne Saußele17, Charles Schiffer23, Richard Silver24, Bengt Simonsson25, Juan-Luis Steegmann26, John M. Goldman27, and Rüdiger Hehlmann17

Abstract
Advances in chronic myeloid leukemia treatment, particularly regarding tyrosine kinase inhibitors (TKIs), mandate regular updating of concepts and management. An ELN expert panel reviewed prior and new studies, to update recommendations made in 2009. We recommend as initial treatment imatinib or nilotinib or dasatinib. Response is assessed with standardized RQ-PCR and/or cytogenetics at 3, 6, and 12 months. BCR-ABL1 transcript levels ≤10% at 3 months, <1% at 6 months, and ≤0.1% from 12 months onward, define optimal response, while >10% at 6 months and >1% from 12 months onward define failure, mandating a change of treatment.

Read full Abstract:
http://bloodjournal.hematologylibrary.org/content/early/2013/06/26/blood...

"Treating Chronic Myeloid Leukemia Improving Management through understanding the patient experiences"

The Chronic Myelogenous Leukemia (CML) Society of Canada is pleased to provide open access to the paper, “Treating Chronic Myeloid Leukemia - Improving Management Through Understanding of the Patient Experience”.

The tremendous progress made in chronic myeloid leukemia (CML) treatment affords patients more options than ever. Five currently available BCR-ABL inhibitors form the mainstay of CML treatment, including first-generation imatinib and more potent second-generation BCR-ABL inhibitors dasatinib and nilotinib, with bosutinib and ponatinib having been recently approved for market inclusion. Studies show that dasatinib and nilotinib exhibit greater efficacy than imatinib in first-line chronic-phase CML (CML-CP), allowing more patients to achieve deeper, more rapid responses associated with improved outcomes.
With alternatives to imatinib for first-line CML-CP and the wealth of information (and misinformation) on the Internet, a tremendous need exists for clear, accurate facts to assist patients in making treatment decisions. Patients appreciate the guidance of their oncology nurse in providing disease, treatment, and monitoring information tailored to meet their needs. Oncology nurses who are able to clearly explain emerging data, including the meaning and significance of faster, deeper responses, will be a valuable resource to their patients.

The paper is written by Cheryl-Anne Simoneau, BA, who is the president and chief executive officer of the Chronic Myeloid Leukemia Society of Canada. Writing and editorial support were provided by Anita Engh, PhD, at Stem Scientific with funding from Bristol-Myers Squibb. The author takes full responsibility for the content of the article. The author did not receive honoraria for this work. The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias.

http://cmlsociety.org/wp-content/uploads/2013/02/Simoneau-Treating-CML.pdf

Landmark analysis of 4-year (y) data from ENESTnd.

Impact of early molecular response to nilotinib (NIL) or imatinib (IM) on the long-term outcomes of newly diagnosed patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP)

2013 ASCO Annual Meeting
Abstract Number: 7054^
Citation: J Clin Oncol 31, 2013 (suppl; abstr 7054^)

Author(s):
Giuseppe Saglio, Timothy P. Hughes, Richard A. Larson, Surapol Issaragrilsil, Anna G. Turkina, Juan Luis Steegmann, Jose L. Lopez, Chiaki Nakaseko, Matt E. Kalaycio, Francoise Huguet, Charisse N. Kemp, Xiaolin Fan, Hans D. Menssen, Hagop M. Kantarjian, Andreas Hochhaus; University of Turin, San Luigi Gonzaga Hospital, Orbassano, Italy; Centre for Cancer Biology, SA Pathology, University of Adelaide, Adelaide, Australia; The University of Chicago, Chicago, IL; Mahidol University, Siriraj Hospital, Bangkok, Thailand; Hematology Research Center, Moscow, Russia; Hospital Universitario de la Princesa, Madrid, Spain; Banco Municipal de Sangre, Dpt. Clinicas Hematologicas, Esq. Pirineos, Caracas, DC, Venezuela; Chiba University Hospital, Department of Hematology, Chiba, Japan; Cleveland Clinic, Cleveland, OH; Hospital de Purpan, Toulouse, France; Novartis Pharmaceuticals Corp, East Hanover, NJ; Novartis Pharma AG, Basel, Switzerland; The University of Texas MD Anderson Cancer Center, Houston, TX; Abteilung Hämatologie/Onkologie, Universitätsklinikum Jena, Jena, Germany

Background: ENESTnd demonstrated the superiority of NIL to IM in pts with newly diagnosed CML-CP, such as higher rates of molecular response (MR) and reduced risk of progression to accelerated phase (AP)/blast crisis (BC). This landmark analysis of ENESTnd is based on BCR-ABL transcript levels at 3 mo, with 4 y of follow-up.

http://meetinglibrary.asco.org/content/112397-132

Plasma trough imatinib levels and molecular response in patients with CML: A single institution study from India.

2013 ASCO Annual Meeting
Abstract Number: 7079
Citation: J Clin Oncol 31, 2013 (suppl; abstr 7079)
Author(s):
Hemant Malhotra, Pratibha Sharma, Shipra Bhargava, Om Singh Rathode, Bharti Malhotra, Vikram Gota; Birla Cancer Center, SMS Medical College Hospital, Jaipur, India; Advanced Research Lab, SMS Medical College, Jaipur, India; Advanced Centre for Treatment, Research, and Education in Cancer, Tata Memorial Center, Navi Mumbai, India

Background: One of the reasons proposed for suboptimal responses in Chronic Myeloid Leukemia (CML) patients receiving standard-dose Imatinib has been low blood levels of the drug. Our study aimed to determine the correlation between mean trough Imatinib plasma levels and molecular response in CML chronic phase patients at our centre. We also attempted to compare imatinib plasma levels in patients receiving Gleevec (Novartis) versus patients who were on the generic version of the drug.

http://meetinglibrary.asco.org/content/116110-132

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:........"

www.clinicaloncology.com/ViewArticle.aspx?d=Hematologic%2bMalignancies&d_id=149&i=May+2013&i_id=960&a_id=23257

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

Significance

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

www.pnas.org/content/early/2013/06/04/1301838110

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