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.
Professor Steve O’Brien, Newcastle University, UK
PF-114, a potent and selective inhibitor of native and mutated BCR/ABL is active against Philadelphia chromosome- positive (Ph+) leukemias harboring the T315I mutation
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
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.
The BCL2 inhibitor ABT-199 significantly enhances imatinib-induced cell death in chronic myeloid leukemia progenitors
Tun Kiat Ko1, Charles T.H. Chuah1,2, John W.J. Huang1 , King-Pan Ng1 and S. Tiong Ong
BCR-ABL1-specific tyrosine kinase inhibitors prolong the life of patients with chronic myeloid leukemia (CML) but cannot completely eradicate CML progenitors. The BH3 mimetic, ABT-263, targets prosurvival BCL2 family members, and has activity against CML progenitors. However, the inhibitory effect of ABT-263 on BCL-XL, which mediates platelet survival, produces dose-limiting thrombocytopenia. A second-generation BH3 mimetic, ABT-199, has been developed to specifically bind BCL2 but not BCL-XL. We determined the activity of ABT-199 against CML cell lines, as well as primary CML and normal cord blood (NCB) progenitors. We find that BCL2 expression levels predict sensitivity to ABT-199 in CML and NCB progenitors, and that high NCB BCL2 levels may explain the reported hematologic toxicities in ABT-199-treated patients. Also, while single agent ABT-199 has modest activity against CML progenitors, when combined with imatinib, ABT-199 significantly enhances imatinib activity against CML progenitors at concentrations predicted to avoid hematologic toxicities.