*Clinical Care Options: Oncology.
In this Expert Analysis, Jorge E. Cortes, MD, and Michael J. Mauro, MD, provide an in-depth review of the most clinically relevant new data presented at the 2013 American Society of Hematology meeting on current and emerging therapies for the treatment of chronic myeloid leukemia.
Avillion Group Partners with Pfizer to Co-develop BOSULIF® (bosutinib) as First-Line Treatment for Patients with Chronic Myelogenous Leukemia
London, UK, January 09, 2014 --
The Avillion Group (Avillion), a co-developer of late-stage clinical assets, announced today that it has entered into an exclusive collaborative development agreement with Pfizer Inc. to conduct a global Phase 3 clinical trial of Pfizer’s BOSULIF® (bosutinib).
The trial, which will be conducted across multiple sites in the United States, Asia and Europe, will evaluate BOSULIF, administered at a starting dose level of 400 mg daily, as a first-line treatment for patients with chronic phase Philadelphia chromosome positive (Ph+) chronic myelogenous leukemia (CML).
Under the terms of the agreement, Avillion will provide the funding for and will conduct the trial to generate the clinical data necessary to potentially support a registration dossier for marketing authorization of BOSULIF by regulatory authorities for an indication as first-line treatment of patients with chronic phase Ph+ CML. If approved for this indication, Avillion will be eligible to receive milestone payments from Pfizer upon regulatory approval of the drug. Pfizer will retain all rights to commercialize BOSULIF globally.
"We are delighted to announce Avillion’s agreement with Pfizer, a global leader in the biopharmaceutical industry, and we look forward to working with them with the goal of advancing the development of BOSULIF and expanding its availability to a broader range of CML patients,” said Lewis Cameron, CEO of Avillion. “Avillion offers pharmaceutical and biotech companies a compelling option to partner late-stage drug development projects. We have an experienced team focused on global drug development and regulatory approval, with the capability to optimise contract research organization (CRO) management.”
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 ...read more
ARIAD Announces the Commercial Availability of Iclusig (Ponatinib) for Patients with Refractory Philadelphia-Positive Leukemias in the U.S.
17th January 2014
CAMBRIDGE, Mass.--(BUSINESS WIRE)-- ARIAD Pharmaceuticals, Inc. (NASDAQ: ARIA) today announced the commercial availability of Iclusig® (ponatinib) for adult patients with refractory chronic myeloid leukemia and Philadelphia-chromosome positive acute lymphoblastic leukemia in the United States. ARIAD has begun shipping Iclusig to Biologics, Inc., its exclusive specialty pharmacy, which is now filling prescriptions from physicians and distributing the cancer medicine to patients.
We are pleased to again have Iclusig commercially available to patients in the United States, stated Marty J. Duvall, executive vice president and chief commercial officer for ARIAD. Iclusig is now in our distribution channel with Biologics, and our dedicated sales force will begin promoting Iclusig immediately. We are highly confident in our commercial launch of Iclusig and look forward to reporting on our progress on a quarterly basis.
Last month, the U.S. Food and Drug Administration (FDA) approved revised U.S. Prescribing Information (USPI) and a communications Risk Evaluation and Mitigation Strategy (REMS) for Iclusig that allowed for the immediate resumption of its marketing and commercial distribution. The USPI includes a revised indication statement and boxed warning, updated safety information and recommendations regarding dosing considerations for prescribers. Iclusig is now indicated for the treatment of adult patients with:
T315I-positive chronic myeloid leukemia (chronic phase, accelerated phase, or blast phase) or T315I-positive Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia, or
Chronic phase, accelerated phase, or blast phase chronic myeloid leukemia or Ph+ acute lymphoblastic leukemia for whom no other tyrosine-kinase inhibitor therapy is indicated.
The starting dose of Iclusig remains 45 mg daily. ...read more
December 31, 2013 | Chronic Myeloid Leukemia, Hematologic Malignancies, Leukemia & Lymphoma
By Dave Levitan
A small, hypolobated megakaryocyte in a bone marrow aspirate, typical ...
Modulation of the bone marrow microenvironment with parathyroid hormone (PTH) may be a feasible way to dramatically reduce counts of leukemia stem cells in chronic myeloid leukemia (CML) patients, according to new research in mice. Reducing leukemia stem cells (LSCs) is a required step on the path to a true cure for the disease.
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.
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.
chronic myeloid leukaemia, drug resistance, prognostic factors, tyrosine kinases
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.
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.'
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
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
* 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.
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.....'