Page 1481 - Williams Hematology ( PDFDrive )

1456 Part X: Malignant Myeloid Diseases Chapter 89: Chronic Myelogenous Leukemia and Related Disorders 1457

“Acquired Resistance” below). The significance also depends on time of Management of side effects is of importance in maintaining a high rate
suboptimal response with earlier time points indicating a worse prog- of adherence.
nosis. Currently, CCyR and PCyR at 3 months are considered optimal
and suboptimal responses. Suboptimal responses are labeled as a “warn- Development of Tyrosine Kinase Inhibitor Resistance
ing” response in the Network guidelines. These response levels may The development of resistance to imatinib is not surprising. 521,522 Its spec-
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trigger ABL mutation analysis or closer monitoring. ificity and “snug fit” into the ABL1-kinase pocket provide the ideal cir-
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cumstance for resistance. Some cases demonstrate primary resistance
Secondary Chromosomal Changes with Tyrosine Kinase to imatinib, and gene profiling has demonstrated differential expression
Inhibitors of about 46 genes in responders compared to nonresponders. Even in
524
Because of its earlier development, most of these data are obtained with patients with CCyR, malignant progenitors at the LTC-IC stage persist.
imatinib treatment. Clonal abnormalities in cells lacking a detectable Chronic phase CML stem cells are resistant to imatinib and are genet-
Ph chromosome or BCR-ABL1 rearrangements have been detected in ically unstable. These cells have a high level of BCR-ABL1 transcrip-
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patients undergoing imatinib therapy who previously were treated with tion, and they are thought to express transporter proteins that result in
IFN-α. 507,508 These cytogenetic changes were noted in seven patients at a abnormal imatinib flux. Mathematical models suggest that imatinib
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median of 13 months of imatinib therapy, and trisomy 8 was the most rapidly eliminates leukemic progenitors, but does not deplete CML stem
507
frequent abnormality. All of these patients had MCyRs to imatinib. The cells. Such models predict the probability of developing resistant muta-
presence of additional chromosomal abnormalities is considered to be a tions and can estimate the time that resistance will emerge. Several
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feature of the accelerated phase of CML. In some patients, clonal evolu- potential mechanisms of resistance include BCR-ABL1 amplification in
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tion may be related to imatinib resistance. Clonal abnormalities may be the presence of imatinib, P-glycoprotein–mediated drug efflux, altered
510
present in up to 10 percent of patients taking imatinib. Some of these drug metabolism, acquisition of BCR-ABL1–independent signaling
cases may be associated with a MDS, especially in those patients with pre- characteristics, and point mutations in the ABL1 kinase domain that
vious exposure to cytarabine and idarubicin. The antiproliferative effect decrease imatinib binding. Each of these mechanisms of resistance may
of imatinib allows restoration of polyclonal hematopoiesis in CCyR, have clinical relevance.
which could permit the manifestation of a Ph chromosome–negative Primary Resistance Primary resistance to imatinib is defined as
disorder. Some investigators have found that, with the possible excep- lack of CHR at 6 months or failure to achieve any level of cytogenetic
511
tion of +8, +Ph, and i(17), additional chromosomal abnormalities at response at 6 months, a MCyR at 12 months, or a CCyR at 18 months.
diagnosis are not associated with an inferior outcome to imatinib ther- This may occur in 15 to 25 percent of patients. Primary resistance may
apy. 512,513 In contrast, another group found that development of trisomy often be the result of inadequate plasma concentration because of bind-
8 in patients taking imatinib, while associated with pancytopenia, did ing of the drug to proteins, such as albumin or α -acid glycoprotein. In
1
not result in signs of disease progression. In a series of 34 CML patients an analysis of the IRIS study, plasma levels of imatinib following the
who developed Ph chromosome–negative clones while taking imatinib, first month of treatment proved to be a significant predictor for clinical
the most common abnormalities were trisomy 8 and monosomy 7. In response. Plasma levels are not available for clinical use, however, so
11 of these patients, no archival evidence of these clones was present these have minimal influence on treatment decisions when responses
before imatinib therapy was initiated, and none of the patients devel- are not as expected. Only one gene, prostaglandin-endoperoxide syn-
514
oped myelodysplasia. In patients treated at diagnosis with imatinib, 9 thase 1/cyclooxygenase1 (PTGS1/COX1) was found to differentiate
percent developed chromosomal abnormalities in Ph chromosome-neg- primary imatinib resistance. Eleven genes were associated with second-
ative metaphases. These appeared at a median of 18 months, and the ary resistance after imatinib therapy in those without an ABL1 kinase
most common abnormalities were −Y and +8. Most were temporary and domain mutation. Expression of the OCT-1, which mediates drug
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disappeared within 5 months. Only one patient with −7 progressed to influx, is thought to be important for imatinib but not dasatinib effec-
515
acute myelogenous leukemia (AML). Cytogenetic clonal evolution may tiveness. 529,530 Many CML patients who have a suboptimal response to
not be an important impediment to achieving a MCyR or CCyR with imatinib have low OCT-1 activity, but this can be overcome with higher
imatinib, but it is an independent poor prognostic factor for survival of doses of imatinib or use of dasatinib, which uptake is not dependent on
516
patients in chronic and accelerated phases of CML. Imatinib therapy OCT-1 expression. OCT-1 expression is associated with MMR at 12
530
may overcome the poor prognostic significance of derivative chromo- and 24 months, and it is a predictor of the long-term risk of resistance
some 9 in CML. 517 and of transformation in patients treated with imatinib. CML CD34+
531
cells overexpress the drug transporter ABCG2, and imatinib, dasatinib,
Adherence to Tyrosine Kinase Inhibitor Therapy and nilotinib are substrates for ABCB1 and ABCG2. Overexpression of
Noncompliance with therapy is associated with poorer outcomes. In MDR1 has been associated with decreased intracellular concentration
one trial, patients with a suboptimal response had higher nonadher- of imatinib. 532
518
ence (23 percent) than did those with optimal responses (7 percent). Acquired Resistance Acquired resistance is that which occurs
In another study, adherence was the only independent predictor for after exposure to TKIs or other treatments. Amplified gene expression
achieving a complete molecular response (CMR) on imatinib. Patients and increased BCR-ABL1 protein expression are often reported in resis-
with an adherence rate of 85 percent or less had a greater chance of tant patients. Duplication of the Ph chromosome and isodicentric chro-
losing their CCyR at 2 years (27 percent) than did those with better mosomes are a possible mechanism of resistance to imatinib. 533,534
adherence (1.5 percent). They, also, had a lower chance of remaining on Mutations in the ABL1 kinase domain are a frequent mechanism of
519
imatinib. Adherence has also been correlated with level of molecular resistance. Kinase domain mutations were the only independent predic-
response. In patients using a TKI for about 5 years, median adherence tor for the loss of CCyR and progression when compared to those with-
was 98 percent (range: 24 to 100 percent). If adherence was greater than out a mutation. Mutations in the ABL1 kinase domain may predate
535
536
90 percent, there was a higher probability for a 3-log reduction in BCR/ imatinib treatment, and several BCR-ABL1 kinase domain mutants
ABL1 transcripts and a CMR. If adherence was less than 80 percent, associated with imatinib resistance remain sensitive to the drug, sug-
no MMRs occurred. The poor adherence to second-generation TKIs gesting a need for characterization before a resistant phenotype can be
520
has not been studied for a sufficient duration to determine its impact. attributed to the given mutation. The mutant clone does not always
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