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).
“The TIDEL-II study aimed to optimize treatment outcomes by maximizing the number of patients reaching [European Leukemia Net] treatment milestones,” wrote study authors led by Timothy P. Hughes, of SA Pathology in Adelaide, Australia. The study built upon TIDEL-I, in which imatinib treatment was intensified based upon early targets.
In the new TIDEL-II study, two sequential cohorts totaling 210 patients with CML were enrolled. All patients in both cohorts began treatment with imatinib 600 mg/day. At 22 days imatinib could be intensified to 800 mg/day if plasma trough levels were below 1,000 ng/ml.
BCR-ABL1 levels (targets included ≤ 10%, ≤ 1%, and ≤ 0.1%) at 3, 6, and 12 months were then used to determine treatment plan. In cohort 1, if patients failed any target they were escalated to imatinib 800 mg/day, and then switched to nilotinib 400 mg twice daily if the same target was failed 3 months later. In cohort 2, failing to hit a target resulted in immediate switching to nilotinib; intolerance or loss of response in either cohort also resulted in switching to nilotinib.
At 12 months, 10% of cohort 1 and 12% of cohort 2 had a confirmed complete molecular response. At 24 months, these rates were 22% and 28%. ...read more
BCR-ABL kinase domain mutation analysis in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors: recommendations from expert panel on behalf of European LeukemiaNet
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
August 4, 2011;
Blood: 118 (5)
Mutations in the Bcr-Abl kinase domain may cause, or contribute to, resistance to tyrosine kinase inhibitors (TKIs) in chronic myeloid leukemia patients. Recommendations aimed to rationalize the use of BCR-ABL mutation testing in chronic myeloid leukemia have been compiled by a panel of experts appointed by the European LeukemiaNet (ELN) and European Treatment and Outcome Study and are here reported. Based on a critical review of the literature and, whenever necessary, on panelists' experience, key issues were identified and discussed concerning: (1) when to perform mutation analysis, (2) how to perform it, and (3) how to translate results into clinical practice. In chronic phase patients receiving imatinib first-line, mutation analysis is recommended only in case of failure or suboptimal response according to the ELN criteria. In imatinib-resistant patients receiving an alternative TKI, mutation analysis is recommended in case of hematologic or cytogenetic failure as provisionally defined by the ELN. The recommended methodology is direct sequencing, although it may be preceded by screening with other techniques, such as denaturing-high performance liquid chromatography. In all the cases outlined within this abstract, a positive result is an indication for therapeutic change. Some specific mutations weigh on TKI selection.
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.
The phase II trial included 76 patients who were at least 65 years old, and all had a stable complete cytogenetic response (CCgR) lasting more than 2 years. The intermittent imatinib regimen was a 1 month on, 1 month off schedule. -
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.
EPIC was a multinational, multicenter, randomized, open-label trial. It included 307 patients, with a median follow-up of only 5.1 months. The trial was terminated in October 2013 after a signal for increased risk of arterial thrombotic events was observed in the ponatinib treatment arm. Because of that early termination, none of the predefined endpoints could be thoroughly analyzed, but researchers presented other relevant data based on a cutoff of April 1, 2014. The analysis, led by Jeffrey H. Lipton, MD, PhD, of Princess Margaret Cancer Centre at the University of Toronto in Canada, was presented at the American Society of Hematology Annual Meeting in San Francisco in December 2014.
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.
Sustained inhibition of STAT5, but not JAK2, is essential for TKI-induced cell death in chronic myeloid leukemia
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.
The chances of patients with Philadelphia chromosome-positive leukemia (Ph+) being cured has greatly increased in recent years. Nevertheless, a high percentage of patients have developed resistance to available medication. But now, haematologists 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, both in vitro and in vivo. They have reported this in the current edition of the specialist journal 'Leukemia'.
Tyrosine Kinase Inhibitors Are Linked to Platelet Dysfunction in Patients with Chronic Myeloid 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.
Wangsuekul Warit, MD, of Chiang Mai University, Chiang Mai, Thailand, explained that TKIs have become a standard of care for CML and possess a favorable safety profile. Dr. Warit said that a CML patient in his clinic who was taking imatinib developed a large retroperitoneal hematoma after oophorectomy. The patient’s platelet count and coagulogram were normal, suggesting platelet dysfunction. Platelet dysfunction has been reported with dasatinib, so the team decided to collect data on the prevalence of platelet dysfunction in patients with CML receiving TKIs in their clinic.