okay everybody knows RESISTENCE happens in CML with the other drugs.
please read this and then know what PONA does. it will take some more time maybe 1-2 more years to play out.
but if you know what you own here the prize is great.
taken from last nights 100 page pona paper. i suggest all read it.
Chronic myeloid leukaemia (CML) is a clonal myeloproliferative disorder representing about 15% to 20% of adult leukaemias (Deininger et al, 2000; Pinilla-Ibarz et al, 2008). The underlying cause of CML is the BCR-ABL fusion oncoprotein, which results from a reciprocal t (9; 22) chromosomal translocation in hematopoietic stem cells. This chromosomal abnormality, known as the Philadelphia chromosome (Ph+), is present in about 95% of all patients with CML, as well as about 20% to 25% of adult patients with acute lymphoblastic leukaemia (ALL). The translocation leads to the fusion of the Breakpoint Cluster Region (BCR) coding sequence with the tyrosine kinase coding region of ABL. This fusion event results in the constitutive activation of ABL kinase activity. BCR-ABL activates multiple downstream pathways that contribute to the growth and survival of cells (Hazlehurst et al, 2009).
Chronic myeloid leukaemia is typically a triphasic continuum of disease with a chronic phase (CP-CML), accelerated phase (AP-CML), and blast phase (BP-CML)—characteristics of the disease and prognosis are different for each phase. Chronic is the longest phase, and can last over 10 years in some patients (Padmanabhan et al, 2008). However, if transition to AP-CML occurs, median survival is typically limited to under a year, while patients in BP-CML (which resembles acute leukaemia) usually live for only a few months. Most patients are diagnosed in CP-CML and may be asymptomatic or present with fatigue, anaemia, weight loss, night sweats, or splenomegaly.
Acute lymphoblastic leukaemia (ALL) is a malignant proliferation of lymphoid cells. The majority of cases of ALL show chromosomal and genetic abnormalities, and approximately 25% of adult cases of ALL are Ph+. The presence of the BCR-ABL translocation confers an adverse prognosis (Radich, 2001).
Current treatment guidelines (European LeukemiaNet and National Comprehensive Cancer Network) recommend treatment with Tyrosine Kinase Inhibitors (TKIs). In Europe the following TKIs are currently approved for the treatment of CML and Ph+ ALL: Glivec (imatinib); Sprycel (dasatinib); and Tasigna (nilotinib).
Treatment for CML was significantly advanced in 2001 following the approval of imatinib. Since then, targeted therapy with imatinib in newly diagnosed patients has become standard. With imatinib the complete cytogenetic response (CCyR) rate was reported as 76% (O’Brien et al., 2003). Dasatinib and nilotinib have also been approved for the treatment of patients who are or become resistant to imatinib therapy. These drugs yield complete cytogenetic response rates (CCyR) from 30%-50% (Talpaz et al., 2006; Kantarjian et al., 2006). Resistance to TKI therapy continues to be a significant challenge in the Iclusig
CHMP assessment report
treatment of CML. At present, there is no standard approach to treat the CML patient who has been treated unsuccessfully with both imatinib and then either with dasatinib or nilotinib.
The best understood mechanism of resistance to TKI therapy is the development of point mutations in the BCR-ABL kinase domain. More than 100 different mutations in the kinase domain of ABL have been discovered and have been shown to be responsible for 40% to 50% of the resistance to existing TKIs (Jabbour et al., 2009). The detection of kinase domain mutations even early in disease is adversely prognostic (Khorashad et al., 2008), is higher in accelerated phase (AP)/blast phase (BP) compared with chronic phase (CP) and increases with the duration of disease (Quintas-Cardama & Cortes, 2008). For patients who fail imatinib therapy, the frequency of BCR-ABL mutations ranges from 40% to 90%, depending on the phase and method of detection (Quintas-Cardama & Cortes, 2008).
The most common single resistant mutation, which occurs in approximately 15% of patients who develop resistance to imatinib (Quintas-Cardama & Cortes, 2008), is a transition point mutation at position 944 of the BCR-ABL gene, resulting in a substitution of isoleucine (I) for threonine (T) at position 315 of the protein: designated T315I, a “gatekeeper” mutation. The T315I mutation accounts for 15%-20% of all mutations observed in refractory CML (Nicolini et al, 2009).
Although dasatinib is effective against some mutations that confer resistance to imatinib therapy, and nilotinib also treats some imatinib-induced mutations, no approved drug inhibits T315I mutation.
However, not all patients who fail therapy carry detectable resistance mutations. Mutations are undetectable in a substantial proportion of patients who fail imatinib. In many of these patients, non BCR ABL driven mechanisms of resistance are likely contributing to resistance.