and Kelvin L. Chou2 (1) Parkinson’s Clinic of Eastern Toronto & Movement Disorders Centre, Toronto, ON, Canada (2) Michigan House, University of Michigan Medical School, Ann Arbor, MI, USA KeywordsEpidemiologyGeneticsPathophysiologyClinical features…
Fig. 7.1 Structure of the BCR–ABL1 fusion gene. Panel (a) illustrates the common breakpoints of the BCR and ABL1 genes; panel (b) shows the common transcipt types. The most common BCR–ABL1 transcripts encountered in CML…
Fig. 3.1 Formation of BCR-AB fusion gene by reciprocal chromosomal translocation t(9;22) and their breakpoints There are several functional domains in BCR-ABL, through which it interacts with downstream signaling molecules…
Fig. 9.1 Overall cytogenetic and molecular response rates of chronic phase CML to ponatinib within the PACE trial [14]. MCyR states for major cytogenetic response, CCyR for complete cytogenetic response,…
Disease phase ELN (2006) WHO (2008) ELN (2013) Accelerated phase Blast cells in blood or bone marrow 15–29 %, or blasts + promyelocyte in blood or marrow >30 %, with blasts <30 % Blast cells…
Fig. 12.1 Rates of treatment-free remission in the (a) STIM and (b) TWISTER clinical trials. Kaplan-Meier estimates of the proportion of patients free of molecular recurrence after imatinib withdrawal. The…
Mechanism of resistance Treatment strategies BCR-ABL1-dependent ABL1-kinase domain mutationsa Second-generation TKIs Ponatinib [77, 78] or allosteric inhibitors BCR–ABL1 amplification BCR-ABL1-independent (intrinsic) Activation of downstream signalling JAK-STAT pathway PI3K/AKT/mTOR pathway JAK2…
Imatinib Nilotinib Dasatinib Bosutinib Ponatinib First line, approved dose 400 mg OD 300 mg BID 100 mg OD NA NA Second line, approved dose 300–400 mg BID 400 mg BID 70 mg BID or 140 mg…
Time First line Second line Optimal response Failure Optimal response Failure Baseline 3 months BCR-ABLIS ≤10 % No CHR BCR-ABLIS ≤10 % No CHR or Ph+ >95 % or mutations Ph+ ≤35 % Ph+ >95 %…
Method Target Sensitivity Advantages Disadvantages Metaphase t(9;22) 1–5 % The gold standard and detection of other chromosomal changes Needs dividing cells, so generally only successful form of bone marrow sample Chromosome…
