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Make a fundraising page JustGiving The CML Support Group is an online patient support group for chronic myeloid leukaemia patients, their families and carers. The website has been running since April 2000 and has a lively discussion forum as well as information regarding current therapies for CML.

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 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

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Drugs to Avoid in Patients on Tyrosine Kinase Inhibitors

Megan Brooks July 25, 2014

With the rapid and widespread uptake of tyrosine kinase inhibitors (TKIs) in oncology over the past several years, serious drug–drug interactions are an "increasing risk," according a new report.
To guarantee the safe use of TKIs, "a drugs review for each patient is needed," write Frank G.A. Jansman, PharmD, PhD, from Deventer Hospital in the Netherlands, and colleagues in a review published in the July issue of the Lancet Oncology.
The review provides a comprehensive overview of known and suspected interactions between TKIs and conventional prescribed drugs, over-the-counter drugs, and herbal medicines.

Drug interactions with the tyrosine kinase inhibitors imatinib, dasatinib, and nilotinib

Amina Haouala1, Nicolas Widmer1, Michel A. Duchosal2, Michael Montemurro3, Thierry Buclin1, and Laurent A. Decosterd1


Several cancer treatments are shifting from traditional, time-limited, nonspecific cytotoxic chemotherapy cycles to continuous oral treatment with specific protein-targeted therapies. In this line, imatinib mesylate, a selective tyrosine kinases inhibitor (TKI), has excellent efficacy in the treatment of chronic myeloid leukemia. It has opened the way to the development of additional TKIs against chronic myeloid leukemia, including nilotinib and dasatinib. TKIs are prescribed for prolonged periods, often in patients with comorbidities. Therefore, they are regularly co-administered along with treatments at risk of drug-drug interactions. This aspect has been partially addressed so far, calling for a comprehensive review of the published data. We review here the available evidence and pharmacologic mechanisms of interactions between imatinib, dasatinib, and nilotinib and widely prescribed co-medications, including known inhibitors or inducers of cytochromes P450 or drug transporters. Information is mostly available for imatinib mesylate, well introduced in clinical practice. Several pharmacokinetic aspects yet remain insufficiently investigated for these drugs. Regular updates will be mandatory and so is the prospective reporting of unexpected clinical observations.

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Effect of imatinib therapy with and without turmeric powder on nitric oxide levels in chronic myeloid leukemia

Ghalaut VS1, Sangwan L, Dahiya K, Ghalaut PS, Dhankhar R, Saharan R.

Nitric oxide (NO) is involved in different stages of malignancies. Increased levels of NO have been reported in different leukemias. Imatinib is the preferred drug for the treatment of chronic myeloid leukemia (CML). Turmeric powder contains curcumin which has anti-leukemic property and also decreases NO synthesis. This study was conducted on fifty patients of CML divided into two groups, group A receiving imatinib alone and group B receiving turmeric powder along with imatinib for six weeks. Nitric oxide levels were estimated in these patients before and after receiving therapy and were analyzed statistically. Nitric oxide levels were found to be significantly decreased in both the groups, but more significantly in group B after receiving the respective treatments. Thus, curcumin acts as an adjuvant to imatinib in decreasing the NO levels and may help in the treatment of CML patients.
PMID: 21844132 [PubMed - indexed for MEDLINE]

MDR1 expression predicts outcome of Ph+ chronic phase CML patients on second-line nilotinib therapy after imatinib failure

M Agrawal1, B Hanfstein1, P Erben1, D Wolf2, T Ernst3, A Fabarius1, S Saussele1, D Purkayastha4, R C Woodman4, W-K Hofmann1, R Hehlmann1, A Hochhaus3 and M C Müller1

Nilotinib was able to impede proliferation of MDR1-overexpressing imatinib-resistant cells. High MDR1 gene expression might identify patients whose mode of imatinib resistance is essentially determined by increased efflux activity of MDR1 and therefore can be overcome by second-line nilotinib treatment.

Deep molecular responses achieved in patients with CML-CP who are switched to nilotinib after long-term imatinib

Timothy P. Hughes1,*, Jeffrey H. Lipton2, Nelson Spector3, Francisco Cervantes4, Ricardo Pasquini5, Nelma Cristina D. Clementino6, Pedro Enrique Dorlhiac Llacer7, Anthony P. Schwarer8, Francois-Xavier Mahon9, Delphine Rea10, Susan Branford11, Das Purkayastha12, LaTonya Collins12, Tomasz Szczudlo12, and Brian Leber13

Key Points
* Nilotinib induced deeper molecular responses than continued imatinib in patients with minimal residual disease on long-term imatinib.
* These deeper responses may enable more patients to benefit from treatment-free remission trials.

Copyright © 2014 American Society of Hematology

Managing children with chronic myeloid leukaemia (CML) Recommendations for the management of CML in children and young people up to the age of 18 years

Josu de la Fuente,1 Andre Baruchel,2 Andrea Biondi,3 Eveline de Bont,4 Marie-Francoise Dresse,5 Meinolf Suttorp6 and
Frederic Millot7 on behalf of the International BFM Group (iBFM) Study Group Chronic Myeloid Leukaemia Committee

Paediatrics Department, Saint Mary Hospital, London, UK, 2Department of Paediatric Haematology, Hopital Robert Debre, Paris,
France, 3 M. Tettamanti Research Centre, Paediatrics Department, University of Milano-Bicocca, Monza, Italy, 4 Department of Paediatric Oncology, Beatrix Children’s Hospital, Groningen, the Netherlands, 5 Department of Paediatric Haematology-Oncology, CHR La Citadelle, Liege, Belgium, 6
Department of Paediatric Haematology & Oncology, University Hospital, Technical University Dresden, Dresden, Germany and 7 Department of Paediatric Oncology, CHU Poitiers, Poitiers, France

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