European Medicines Agency recommends further measures to minimise risk of blood vessel blockage with Iclusig
The European Medicines Agency (EMA) has concluded its review of the benefits and risks of Iclusig (ponatinib), a medicine used for the treatment of leukaemia (cancer of the white blood cells), and has recommended strengthened warnings in the product information aimed at minimising the risk of blood clots and blockages in the arteries.
Iclusig is authorised for use in patients with chronic myeloid leukaemia (CML) and acute lymphoblastic leukaemia (ALL) who cannot take or tolerate several other medicines of the same class (known as ‘tyrosine-kinase inhibitors’). The review followed a previous assessment of clinical trial data which indicated that cases of blood clots and blockages in the arteries or veins were occurring at a higher rate than was observed at the time of the medicine’s initial authorisation.
The available evidence shows that the risk of blood vessel blockage with Iclusig is likely to be dose-related, however the data are insufficient to formally recommend the use of lower doses of Iclusig, and there is a risk that lower doses might not be as effective in all patients and in long-term treatment. Therefore, the recommended starting dose of Iclusig should remain 45 mg once a day. The product information will be updated with strengthened warnings about the risks with Iclusig, and to also provide healthcare professionals with the latest evidence in case they wish to consider reducing the dose of Iclusig in patients with ‘chronic phase’ CML who are responding well to treatment, and who might be at particular risk of blood vessel blockage. Additionally, healthcare professionals should stop Iclusig if a complete response has not occurred within three months of treatment, and should monitor patients for high blood pressure or signs of heart problems. ...read more
Treatment Recommendations for People Living with CML
This is a summary of the European public assessment report (EPAR) for Imatinib Teva. It explains how the Committee for Medicinal Products for Human Use (CHMP) assessed the medicine to reach its opinion in favour of granting a marketing authorisation and its recommendations on the conditions of
use for Imatinib Teva.
Timothy Hughes and Deborah White.
South Australian Health and Medical Research Institute, SA Pathology, and University of Adelaide, Adelaide, Australia
With the approval in many countries of nilotinib and dasatinib for frontline therapy in chronic myeloid leukemia,
clinicians now have to make a difficult choice. Because none of the 3 available tyrosine kinase inhibitors (TKIs) have
shown a clear survival advantage, they all represent reasonable choices. However, in individual patients, the case may
be stronger for a particular TKI. In the younger patient, in whom the prospect of eventually achieving treatment-free
remission is likely to be of great importance, dasatinib or nilotinib may be preferred, although their advantage over
imatinib in this setting remains to be proven. In patients with a higher risk of transformation (which is currently based
on prognostic scoring), the more potent TKIs may be preferred because they appear to be more effective at reducing
the risk of transformation to BC. However, imatinib still represents an excellent choice for many chronic myeloid
leukemia patients. All of these considerations need to be made in the context of the patient’s comorbidities, which may
lead to one or more TKIs being ruled out of contention. Whatever first choice of TKI is made, treatment failure or
intolerance must be recognized early because a prompt switch to another TKI likely provides the best chance of
achieving optimal response.
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10 Mar 2014
Researchers in Manchester have investigated the stickiness of leukaemia cells, and whether this is linked to drug resistance.
Chronic myeloid leukaemia (CML) is associated with a specific genetic mutation that results from DNA on different chromosomes breaking off and swapping places. This disrupts genes at the breakpoint and the rejoining point. One of these disrupted genes is called BCR-ABL and drugs that target this mutation have transformed the treatment of CML. However, patients can develop resistance to these drugs, which causes their cancer to return.
Now scientists from The University of Manchester – part of the Manchester Cancer Research Centre - have measured the levels of the BCR-ABL genetic mutation in a cell model of CML. In particular, they separated cells into those that stuck to plastic – “sticky”, or adherent, cells – and those non-adherent ones that did not, and looked for differences between the two groups of cells.
News | September 03, 2014 | Leukemia & Lymphoma, Chronic Myeloid Leukemia, Hematologic Malignancies
By Dave Levitan
STAT3 inhibition using a novel compound restored sensitivity to tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia (CML) cells that had shown resistance independent of BCR-ABL1 kinase activity, according to a new study published in the journal Leukemia. The findings could help fill gaps in CML treatment for patients with unexplained resistance to TKIs.
Though TKIs have revolutionized the treatment of CML, between 20% and 30% of patients fail on imatinib due to primary or acquired resistance. “BCR-ABL1 point mutations fail to explain many cases of clinical TKI failure, as many patients with resistance express exclusively native BCR-ABL1,” wrote study authors led by Michael W. Deininger, MD, PhD, of Huntsman Cancer Institute at the University of Utah in Salt Lake City. In such patients where resistance is independent of BCR-ABL1, the researchers hypothesized that targeting the signal transducer and activator of transcription 3 (STAT3) pathway may eliminate that resistance.
The group used structure-activity relationship (SAR) studies and compound library screens to identify BP-5-087, “a potent and selective STAT3 inhibitor.” They confirmed that this molecule binds to the STAT3 SH2 domain using both computation simulations and hydrogen-deuterium exchange assays.
They then tested the effects of BP-5-087 on primary CML cells from newly diagnosed patients. In treatment-naive cells, it had little effect, but in combination with imatinib it reduced formation of cells by 56%. It also showed good activity along with imatinib in CML cells with intrinsic TKI resistance (meaning, independent of BCR-ABL1). The effect was seen in both CML progenitor cells and in leukemic stem cells. ...read more
Sustained inhibition of STAT5, but not JAK2, is essential for TKI-induced cell death in chronic myeloid leukemia
L Schafranek1,2,3, E Nievergall1,2,3, J A Powell4,5, D K Hiwase3,6, T Leclercq1,3, T P Hughes1,2,3,6,7 and D L White1,2,3,4
Kinase inhibitors block proliferative signals in BCR-ABL1+ leukemic cells, but their capacity to induce apoptosis is poorly understood. Initial studies suggested that very brief exposure to kinase inhibitors was sufficient to induce apoptosis in chronic myeloid leukemia (CML) cells. However, flaws in this experimental model have subsequently been identified, leading to the conclusion that apoptosis only occurs with sustained low-level kinase inhibition. Thus, the minimum duration of complete kinase inhibition required to commit CML cells to death is unknown. Here we confirm that <1 h is insufficient to induce significant commitment to death in BCR-ABL1+ cell lines and in primary CD34+ progenitor cells, and establish that commitment to cell death only occurs if kinase inhibition is maintained for 4 h or more. Remarkably, signal transducer and activator of transcription 5 (STAT5) inhibition in combination with transient (<1 h) tyrosine kinase inhibitor (TKI) exposure proved lethal for CML progenitors, despite the reactivation of Bcr-Abl after 1 h. JAK kinase inhibition did not induce cell death in combination with transient TKI exposure. Thus, STAT5 appears to be a critical determinant of the time-dependent sensitivity of CML progenitor cells to TKI treatment in a Bcr-Abl-dependent, but JAK-independent, manner. We conclude that combining kinase inhibition with STAT5 inhibition represents a promising therapeutic approach in BCR-ABL1+ leukemias.
Alternative approaches to eradicating the malignant clone in chronic myeloid leukemia: tyrosine-kinase inhibitor combinations and beyond
Wesam Ahmed and Richard A. Van Etten
Hematology 2013 2013:189-200; doi:10.1182/asheducation-2013.1.189
In patients with chronic myeloid leukemia (CML) in chronic phase who have achieved complete molecular remission on imatinib therapy, clinical trials from France and Australia have demonstrated that the majority experience prompt molecular relapse of their leukemia upon discontinuation of the drug, showing that long-term monotherapy with tyrosine kinase inhibitors is not curative in the majority of patients with CML. This has focused attention on strategies to eradicate residual disease in CML that is presumed to arise from malignant Ph+ stem cells, which should result in permanent cure and long-term leukemia-free survival. Here, we review the evidence that targeting CML stem cells will be of clinical benefit and discuss pharmacological and immunological approaches to accomplish this goal. Where possible, we link preclinical studies of CML stem cell biology to emerging results from clinical trials of agents that may target these cells.
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Conclusions and future directions: getting into the clinic ...read more
Safety of bosutinib versus imatinib in the phase 3 BELA trial in newly diagnosed chronic phase chronic myeloid leukemia
Carlo Gambacorti-Passerini1,*, Jorge E. Cortes2, Jeff H. Lipton3, Anna Dmoszynska4, Raymond S. Wong5, Victor Rossiev6, Dmitri Pavlov7, Karin Gogat Marchant8, Ladan Duvillié8, Navin Khattry9, Hagop M. Kantarjian2 andTim H. Brümmendorf10,11
Article first published online: 21 JUL 2014
Abstract ...read more