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.
This article is a retrospective, single-institution review of the incidence and clinical characteristics of late chronic anemia associated with prolonged use of imatinib for patients with chronic myeloid leukemia. The authors reported a 30% incidence of late chronic anemia associated with a prolonged use of imatinib, with no effect on overall survival.
Larger studies are needed to further evaluate the association before a more definitive answer can be determined.
– Jarett Feldman, MD
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.
read full article:
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.