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A common novel splice variant of SLC22A1 (OCT1) is associated with impaired responses to imatinib in patients with chronic myeloid leukaemia.

Br J Haematol. 2013 Dec;163(5):631-9. doi: 10.1111/bjh.12591. Epub 2013 Oct 10.

Grinfeld J, Gerrard G, Alikian M, Alonso-Dominguez J, Ale S, Valgañon M, Nteliopoulos G, White D, Marin D, Hedgley C, O'Brien S, Clark R, Goldman JM, Milojkovic D, Apperley JF, Foroni L.

Abstract

Approximately one-third of patients with chronic myeloid leukaemia will fail to achieve or maintain responses to imatinib. Changes in solute carrier family 22 (organic cation transporter), member 1 (SLC22A1, also termed OCT1), the main transporter for imatinib, have been proposed as a possible predictive factor. We analysed SLC22A1 mRNA levels and single nucleotide polymorphisms (SNPs) located in exon 7 in 153 diagnostic whole blood samples from two patient cohorts. The level of SLC22A1 expression did not significantly correlate with imatinib failure or achievement of molecular remission. The SNP 408V>M (g.1222G>A) was present in 65% of patients and was associated in all cases with an eight base-pair insertion (8(+) allele) at the 3' end of exon 7. The latter generates an alternative splice site, leading to a premature stop codon. M420del was found in 33% of patients and never in cis with 8(+) (the 3(-) allele). Significantly longer times to 1% and 0·1% molecular responses (by quantitative reverse transcription polymerase chain reaction) were seen in patients with 8(+) 8(+) or 8(+) N compared to those with the remaining four genotypes (N = no insertion or deletion). Patients lacking 8(+) and 3(-) (NN, 18%) showed the best outcomes overall. Thus, while SLC22A1 expression does not appear to affect response, alterations in its splicing or amino acid sequence may do so. © 2013 John Wiley & Sons Ltd.

KEYWORDS:
chronic myeloid leukaemia, drug resistance, prognostic factors, tyrosine kinases

http://www.ncbi.nlm.nih.gov/pubmed/24117365

Penn Medicine Team Reports Findings from Research Study

Results of study: Personalized Cellular Therapy CTL019

NEW ORLEANS — Three and a half years after beginning a clinical trial which demonstrated the first successful and sustained use of genetically engineered T cells to fight leukemia, a research team from the Perelman School of Medicine at the University of Pennsylvania and the Children’s Hospital of Philadelphia will today announce the latest results of studies involving both adults and children with advanced blood cancers that have failed to respond to standard therapies. The findings from the first 59 patients who received this investigational, personalized cellular therapy, known as CTL019, will be presented during the American Society of Hematology’s Annual Meeting and Exposition in New Orleans.

http://www.uphs.upenn.edu/news/News_Releases/2013/12/ctl019/

ASH 2013: CML Relevant Abstracts

254 Any BCR-ABL Reduction Below 10% At 6 Months Of Therapy Significantly Improves Outcome For CML Patients With a Poor Response At 3 Months.
Authors: S Branford, N Roberts, DT Yeung, et al

'..........Our data confirms the importance of achieving BCR-ABL values of 10% or below at 3 mo after starting therapy. Based on the 3 mo assessment, the prognosis was significantly superior for these pts. Progression before the 6 mo time point occurred in 4% of pts with BCR-ABL >10% at 3 mo. However, the vast majority of pts with >10% at 3 mo continued therapy and the 6 mo BCR-ABL assessment provided important long-term prognostic information. Any reduction below 10% at 6 mo led to significantly superior outcomes, approximating those with optimal response at 3 mo. The impact and optimal timing of therapeutic intervention for pts in the poor risk category at 3 mo still needs to be determined in prospective studies and may require large patient cohorts. However, pts who are >10% at both 3 and 6 mo have inferior outcomes and are undoubtedly in need of a therapy change.'

https://ash.confex.com/ash/2013/webprogram/Paper58808.html

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257 Nilotinib Exerts Direct Pro-Atherogenic and Anti-Angiogenic Effects On Vascular Endothelial Cells: A Potential Explanation For Drug-Induced Vasculopathy In CML.
Authors: H Emir, K Albrecht-Schgoer, K Huber, et al ...read more

Ariad gets positive CHMP opinion for continued Iclusig (ponatinib) availability

22/11/2013
European Medicines Agency recommends changes in use of leukaemia medicine Iclusig (ponatinib) in order to minimise risk of blood clots

The European Medicines Agency’s Committee for Medicinal Products for Human Use (CHMP) has made a number of recommendations to help minimise the risk of blood clots obstructing arteries or veins in patients taking the leukaemia medicine Iclusig.

The CHMP recommends that Iclusig should not be used in patients who have had a heart attack or stroke in the past, unless the potential benefits to them outweigh the risks. In addition, the cardiovascular risks of all patients should be assessed and measures should be taken to reduce risks before starting and during treatment with Iclusig. Patients who have high blood pressure should have their blood pressure controlled, and treatment with Iclusig should be stopped immediately in any patient with signs of blood clots obstructing arteries or veins. Further details on these recommendations can be found below.

The CHMP’s recommendations follow a review of updated clinical trial data indicating that blood clots were occurring at a higher rate than was observed at the time of the medicine’s initial authorisation. Conditions related to blood clots, such as heart attacks and strokes, were already considered to be possible side effects of Iclusig and were listed in the EU product information.

Since the medicine’s initial approval in July 2013, its use has been limited to patients who could not be treated with other medicines of the same class, for example, because patients were intolerant to the other medicines or their disease was resistant to them.

The CHMP recommendations are broadly in line with previous advice of the Agency’s Pharmacovigilance Risk Assessment Committee (PRAC) and an opinion will be sent to the European Commission for an update of the EU product information. ...read more

Safety and efficacy of imatinib cessation for CML patients with stable undetectable MRD: results from the TWISTER Study

David M. Ross1,*, Susan Branford2, John F. Seymour3, Anthony P. Schwarer4, Christopher Arthur5, David T. Yeung6, Phuong Dang1, Jarrad M. Goyne1, Cassandra Slader7, Robin J. Filshie8, Anthony K. Mills9, Junia V. Melo10, Deborah L. White1, Andrew P. Grigg11, and Timothy P. Hughes1

Key points

* Around 40% of patients with undetectable minimal residual disease on imatinib can stop treatment without loss of molecular response.

* Patients in treatment-free remission (TFR) still have detectable BCR-ABL DNA several years after stopping imatinib.

Abstract
read more..........
http://bloodjournal.hematologylibrary.org/content/early/2013/05/23/blood...

Related article:

TWIST it but don’t spin it
Jane F. Apperley

'.........This is the first prospective study to confirm the observations of the Stop Imatinib (STIM) study, in which 40% of patients who had achieved deep molecular responses (MRs) on imatinib could discontinue the drug without experiencing relapse,2 which led to speculation that “cure” could be achieved by using oral tyrosine kinase inhibitors (TKIs) alone. Subsequently, randomized phase 3 studies comparing the more potent second generation TKI (2GTKI) with imatinib as first-line therapy showed that these very deep responses were obtained more rapidly and probably in a higher proportion of patients than with imatinib3,4 and resulted in the dilemma currently besetting chronic myeloid leukemia patients and their physicians, namely the choice of the first-line agent.....'

full article....
http://bloodjournal.hematologylibrary.org/content/122/4/470.full

European Medicines Aagency- PRAC update on use of ponatinib -Iclusig

08/11/2013
PRAC updates on the risks of serious vascular occlusive events associated with cancer medicine Iclusig

Modification of product information under way to include strengthened warnings

The European Medicines Agency’s Pharmacovigilance Risk Assessment Committee (PRAC), at its 4-7 November meeting, reviewed new information on the cancer medicine Iclusig (ponatinib) that suggests that side effects such as vascular occlusive events (blood clots obstructing the arteries or veins) occur at a higher rate than initially observed at the time of granting the European Union (EU) marketing authorisation in July 2013.

Conditions related to thrombosis such as myocardial infarction (heart attack) are known side effects of Iclusig and the current EU product information mentions the risk of myocardial infarction, cerebral infarction (stroke) and related disorders.

The PRAC advice is that patients and healthcare professionals may continue to use this medicine with increased caution in its authorised use and should monitor carefully for evidence of thromboembolism (formation of blood clots in the veins and arteries) and vascular occlusion.

read full press release here:
http://www.ema.europa.eu/ema/index.jsp?curl=pages/news_and_events/news/2...

Bone Drug Kills Leukemia in Mice

A bone drug already on the market for osteoporosis may kill chronic myelogenous leukemia (CML) stem cells thought to persist in the bone marrow after standard therapy, lowering the likelihood of disease recurrence, according to a new study in mice led by researchers at Massachusetts General Hospital, the Harvard Stem Cell Institute and the Harvard Department of Stem Cell and Regenerative Biology.

The study, published in Nature Medicine, provides the first evidence in mice that altering the bone environment to make it inhospitable to leukemia stem cells can improve CML outcomes. Current CML treatments effectively target leukemia cells but not leukemia stem cells, and therefore the disease is rarely cured, the study authors said.

The research also suggests that CML and a related, more severe disease— acute myeloid leukemia (AML)— are sensitive to different changes in the bone marrow environment and may therefore require different treatment approaches.

“Traditionally, cancer therapies have always tried to target the cancer cells themselves,” said David Scadden, HMS Gerald and Darlene Jordan Professor of Medicine at Mass General and senior author of the paper. “Our work shows there might be value in targeting the cancer’s home environment as well, in combination.”

“We stepped outside the box to show it’s not all about the tumor, it’s also about where it sits,” added Daniela Krause, HMS instructor in pathology at Mass General and first author of the paper. “That hadn’t been shown before in leukemia.”

http://www.biosciencetechnology.com/news/2013/11/bone-drug-kills-leukemi...

Ponatinib Manufacturer Suspends Distribution

Silas Inman
Published Online: Thursday, October 31, 2013

Marketing and commercial distribution of ponatinib (Iclusig) has been temporarily suspended, following an ongoing FDA investigation that revealed an increased frequency of severe arterial thrombosis and stenosis.

The clinical development of ponatinib was placed on hold in early October, while the FDA investigated the adverse events associated with the drug. This was shortly followed by the early termination of the phase III EPIC trial, which was examining ponatinib in the frontline setting for untreated patients with chronic myeloid leukemia (CML). The suspension in distribution followed discussions between the manufacturer, Ariad Pharmaceuticals, Inc., and the FDA.

The FDA will continue to evaluate whether the benefits of treatment outweigh the risks. At this point, an effective dose and duration of treatment has yet to be identified.

"We continue to work with the FDA to negotiate updates to the US prescribing information for Iclusig and implementation of a comprehensive risk mitigation strategy," Harvey J. Berger, MD, chairman and chief executive officer of Ariad, said in a webcast. "Dialogue with the FDA will continue. We believe there are patients for whom there is a positive risk-benefit profile."

Ponatinib was granted accelerated approval in December 2012 for patients with CML or Philadelphia chromosome–positive acute lymphoblastic leukemia. This approval was based on data from the phase II PACE trial, which enrolled patients who were resistant or intolerant to dasatinib or nilotinib, or harbored a T315I mutation.

http://www.onclive.com/web-exclusives/Ponatinib-Manufacturer-Suspends-Di...

FDA Drug Safety Communication: FDA asks manufacturer of the leukemia drug Iclusig (ponatinib) to suspend marketing and sales

This update is in follow-up to the FDA Drug Safety Communication: FDA investigating leukemia drug Iclusig (ponatinib) after increased reports of serious blood clots in arteries and veins issued on October 11, 2013.

Safety Announcement
[31st October 2013]

The U.S. Food and Drug Administration (FDA) has asked the manufacturer of the leukemia chemotherapy drug Iclusig (ponatinib) to suspend marketing and sales of Iclusig because of the risk of life-threatening blood clots and severe narrowing of blood vessels. We will continue to evaluate the drug to further understand its risks and potential patient populations in which the benefits of the drug may outweigh the risks. Patients currently receiving Iclusig should discuss with their health care professionals the risks and benefits of continuing treatment with the drug.

The drug manufacturer, Ariad Pharmaceuticals, has agreed to FDA’s request to suspend marketing and sales of Iclusig while we continue to evaluate the safety of the drug. At this time, patients and health care professionals should follow FDA’s new recommendations for the drug:

Patients currently taking Iclusig who are not responding to the drug should immediately discontinue treatment and discuss alternative treatment options with their health care professionals. ...read more

Clinical pharmacokinetics of tyrosine kinase inhibitors: implications for therapeutic drug monitoring.

Josephs DH, Fisher DS, Spicer J, Flanagan RJ.

*Department of Medical Oncology, Guy's and St Thomas' Hospital NHS Foundation Trust, London, United Kingdom; and †Toxicology Unit, Department of Clinical Biochemistry, Bessemer Wing, King's College Hospital NHS Foundation Trust, London, United Kingdom.
Abstract ...read more

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