C M Lucas1, R J Harris1, A K Holcroft1, L J Scott1, N Carmell1, E McDonald1, F Polydoros2 and R E Clark1

1Section of Haematology, Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, UK
2CR-UK Liverpool Cancer Trials Unit, University of Liverpool

High CIP2A protein levels at diagnosis of chronic myeloid leukaemia (CML) are predictive of disease progression in imatinib treated patients. It is not known whether this is true in patients treated with second generation tyrosine kinase inhibitors (2G TKI) from diagnosis, and whether 2G TKIs modulate the CIP2A pathway. Here, we show that patients with high diagnostic CIP2A levels who receive a 2G TKI do not progress, unlike those treated with imatinib (P=<0.0001). 2G TKIs induce more potent suppression of CIP2A and c-Myc than imatinib. The transcription factor E2F1 is elevated in high CIP2A patients and following 1 month of in vivo treatment 2G TKIs suppress E2F1 and reduce CIP2A; these effects are not seen with imatinib. Silencing of CIP2A, c-Myc or E2F1 in K562 cells or CML CD34+ cells reactivates PP2A leading to BCR-ABL suppression. CIP2A increases proliferation and this is only reduced by 2G TKIs. Patients with high CIP2A levels should be offered 2G TKI treatment in preference to imatinib. 2G TKIs disrupt the CIP2A/c-Myc/E2F1 positive-feedback loop, leading to lower disease progression risk. The data supports the view that CIP2A inhibits PP2Ac, stabilising E2F1, creating a CIP2A/c-Myc/E2F1 positive-feedback loop which imatinib cannot overcome.

News | March 17, 2015 | Chronic Myeloid Leukemia, Hematologic Malignancies, Leukemia & Lymphoma
By Cancer Network Staff

A single-arm, open-label trial in Australia found that selective early switching from imatinib to nilotinib is feasible and effective in patients with chronic myeloid leukemia (CML).

Simona Soverini1, Andreas Hochhaus2, Franck E. Nicolini3, Franz Gruber4, Thoralf Lange5, Giuseppe Saglio6, Fabrizio Pane7,8, Martin C. Müller9, Thomas Ernst2, Gianantonio Rosti1, Kimmo Porkka10, Michele Baccarani1, Nicholas C. P. Cross11,12, and Giovanni Martinelli1

There has been substantial interest in intermittent or other alternative scheduling of tyrosine kinase inhibitors in treatment for CML. The success of the drugs has been remarkable, but because of that success and the relative young age of many CML patients, many are forced to take the drugs for many years and even decades. This carries high financial burden, as well as increasing chances of non-compliance. Affirming the safety of intermittent scheduling could ease some of those concerns in CML patients.

January 13, 2015 | Chronic Myeloid Leukemia, ASH 2014, Hematologic Malignancies, Leukemia & Lymphoma
By Dave Levitan

Despite the early termination of a phase III trial due to safety concerns, an analysis suggests that ponatinib offers improved efficacy over imatinib in patients with newly diagnosed chronic-phase chronic myeloid leukemia (CP-CML). That improvement comes at the expense of higher rates of adverse events, according to the EPIC trial.

The tyrosine kinase inhibitor (TKI) imatinib has revolutionized the management of chronic myeloid leukaemia (CML). However, around 25% of patients fail to sustain an adequate response. We sought to identify gene-expression biomarkers that could be used to predict imatinib response. The expression of 29 genes, previously implicated in CML pathogenesis, were measured by TaqMan Low Density Array in 73 CML patient samples. Patients were divided into low and high expression for each gene and imatinib failure (IF), probability of achieving CCyR, progression free survival and CML related OS were compared by Kaplan-Meier and log-rank. Results were validated in a second cohort of 56 patients, with a further technical validation using custom gene-expression assays in a conventional RT-qPCR in a sub-cohort of 37 patients. Patients with low PTCH1 expression showed a worse clinical response for all variables in all cohorts. PTCH1 was the most significant predictor in the multivariate analysis compared with Sokal, age and EUTOS. PTCH1 expression assay showed the adequate sensitivity, specificity and predictive values to predict for IF. Given the different treatments available for CML, measuring PTCH1 expression at diagnosis may help establish who will benefit best from imatinib and who is better selected for second generation TKI.

L Schafranek E Nievergall, J A Powell D K Hiwase T Leclercq T P Hughes and D L White

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.

November 28, 2014

Hematologists from Goethe University Frankfurt, working with a Russian pharmaceutical company, have developed a new active substance that effectively combats the most aggressive forms of Philadelphia chromosome-positive leukemia.

Practice Update Editorial Team, 2014 Dec 07

December 7, 2014 – San Francisco, California – A high prevalence of platelet dysfunction has been demonstrated in patients with chronic myeloid leukemia (CML) receiving all types of tyrosine kinase inhibitors (TKIs), including imatinib. This conclusion of a descriptive, cross-sectional study was reported at the 56th American Society of Hematology Annual Meeting and Exposition in San Francisco from December 6 – 9, 2014.

A A Mian1, A Rafiei1, I Haberbosch1, A Zeifman2,3, I Titov2,3, V Stroylov2,3, A Metodieva1, O Stroganov2,3, F Novikov2,3, B Brill4, G Chilov2,3, D Hoelzer1, O G Ottmann1 and M Ruthardt1



1Department of Hematology, Goethe University, Frankfurt, Germany
2Fusion Pharma, LLC, Moscow, Russian Federation
3Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Moscow, Russian Federation
4Institute for Biomedical Research, Georg-Speyer-Haus, Frankfurt, Germany


Abstract
Targeting BCR/ABL with tyrosine kinase inhibitors (TKIs) is a proven concept for the treatment of Philadelphia chromosome-positive (Ph+) leukemias. Resistance attributable to either kinase mutations in BCR/ABL or non-mutational mechanisms remains the major clinical challenge. With the exception of ponatinib, all approved TKIs are unable to inhibit the ‘gatekeeper’ mutation T315I. However, a broad spectrum of kinase inhibition increases the off target effects of TKIs and may be responsible for cardiovascular issues of ponatinib. Thus, there is a need for more selective options for the treatment of resistant Ph+ leukemias. PF-114 is a novel TKI developed with the specifications of i.) targeting T315I and other resistance mutations in BCR/ABL; ii.) achieving a high selectivity to improve safety; and iii.) overcoming non-mutational resistance in Ph+ leukemias.