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1452 Part X: Malignant Myeloid Diseases Chapter 89: Chronic Myelogenous Leukemia and Related Disorders 1453

Weight gain is the most common side effect of imatinib. In patients Pharmacokinetic Considerations During Imatinib Therapy
435
who were older than age 60 years, similar cytogenetic response rates Mean plasma trough concentration of imatinib and its metabolite,
and survival rates were noted as in younger patients in the late chronic CGP74588, obtained at about 1 month (presumptive steady-state) was
phase who were treated concurrently, suggesting that age is not usually 979 ± 530 ng/mL. The rate of CCyR and MMR was higher within the
a factor in response. 436,437 highest quartiles of imatinib trough levels. Some therapists suggest
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that imatinib plasma levels be checked in cases of suboptimal response
Side Effects and Special Treatment Considerations in order to adjust the dose, but access to this monitoring is not rou-
467
Imatinib is usually tolerated. Most adverse effects are manageable and sel- tinely available. Comedications and population covariates, such as
dom require permanent cessation of therapy. Reduction to subtherapeu- body weight and white cell count, had no, or minimal, effect on imatinib
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tic doses is not recommended; it is better to interrupt therapy for a time. 438 clearance. Patients with CML on hemodialysis have been successfully
469
Myelosuppression is common, especially at treatment onset when treated with imatinib. Therapy interruptions and nonadherence with
the CML clone accounts for most of the blood cells. Dose reduction to oral imatinib usage are common, and patient education and close mon-
less than 300 mg/day is not advisable for myelosuppression. The drug itoring are important to ensure compliance. 470
should be stopped until blood counts recover. G-CSF or GM-CSF can
prevent or treat neutropenia. 439,440 Platelet transfusion may be used Initiation of Therapy with Newer Tyrosine Kinase Inhibitors
for severe thrombocytopenia. Patients with imatinib-induced chronic Dasatinib Dasatinib is a second-generation oral BCR-ABL1 inhibitor
441
cytopenias have inferior responses. Myelosuppression is an indepen- with dual inhibition of ABL1 and SRC. It can bind to both the active
471
dent adverse factor for achieving cytogenetic responses with imatinib. and inactive conformation of the ABL1 kinase domain, so it may be
442
Erythropoiesis-stimulating agents may be used to raise hemoglobin affected by mutations resulting in resistance. 471
levels, and their use does not appear to affect CML outcomes, but may Dasatinib was first studied for use in initial therapy in a phase II
443
increase the risk of thrombosis. Severe irreversible marrow aplasias trial that accrued 62 patients. Ninety-eight percent achieved a CCyR,
after imatinib exposure can occur. 444 and the median time to CCyR was 3 months. The MMR rate was 82
The main side effects noted with imatinib include fatigue, edema, percent. Responses were durable, and the recommended treatment
445
nausea, diarrhea, muscle cramps, and rash. Elevated hepatic tran- schedule based on a safety profile was 100 mg, once daily. A random-
472
saminases can occur. Mild transaminase elevations often respond ized, phase III trial compared the efficacy of dasatinib to imatinib. In
473
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to glucocorticoid use. Hepatotoxicity is uncommon, occurring in this study, 259 patients received dasatinib, 100 mg/day, and 260 received
approximately 3 percent of patients, usually within 6 months of onset of imatinib, 400 mg/day. After 12 months of followup, the rates of CCyR by
imatinib use. Acute liver failure has been described. The severe peri- 3, 6, and 9 months were 54, 73, and 78 percent, respectively, for patients
447
orbital edema occasionally observed is postulated to be a drug effect on dasatinib as compared to 31, 59, and 67 percent, respectively, for those
on the function of platelet-derived growth factor receptor (PDGFR) on imatinib. The 24-month CCyR was 80 percent for patients using dasa-
and KIT expressed by dermal dendrocytes. Surgical decompression of tinib, as compared to 74 percent for those on imatinib. The MMR showed
severe edema rarely has been required. Although no effects on sper- a similar trend, and the median time to MMR was 15 months for those
448
matogenesis have been reported, women of childbearing age are at risk using dasatinib, compared to 36 months for those using imatinib.
of teratogenic effects on their fetus. 448 Long-term followup data have confirmed faster and deeper
Weight gain is associated with imatinib use. Patients with renal responses to dasatinib as compared to imatinib. At 4 years, 76 percent
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impairment require lower doses of imatinib. Hypophosphatemia of dasatinib-treated patients had attained a MMR (BCR/ABL1 <0.1 per-
and altered bone and mineral metabolism have occurred. 452,453 Cutane- cent) as compared to 63 percent using imatinib. At 3, 6, and 12 months,
ous reactions with imatinib therapy occur in approximately 15 percent more patients achieved molecular responses using dasatinib than those
454
of patients. Except for severe reactions (approximately 5 percent of using imatinib. There were fewer patients who progressed to accelerated
patients), such as Stevens-Johnson syndrome, exfoliative dermatitis, or blast phase using dasatinib as compared to imatinib. To date, there
and erythema multiforme, cutaneous reactions rarely require perma- is no difference in progression-free survival or overall survival between
nent discontinuation of therapy. With milder reactions, concomitant the two groups. In a randomized study, with a minimal followup of
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glucocorticoid therapy or brief discontinuation of imatinib with gradual 3 years, the proportion of patients with BCR-ABL1 transcript levels
reintroduction at a lower dose and then a gradual increase in dose can less than 10 percent was higher in those using dasatinib as compared
be accomplished. 456,457 With very mild cases, concurrent treatment with to those using imatinib. Better responses were observed at 3, 6, and
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antihistamine or other symptomatic therapy may be successful. Oral 12 months in the patients using dasatinib. The achievement of an early
desensitization regimens have been described that allow some patients molecular response was predictive of improved progression-free and
458
to continue imatinib therapy. Hair depigmentation and hypopigmen- overall survival. 476
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tation of the skin, probably related to the inhibition of the KIT recep- Toxicity of Dasatinib Most grade 3 or 4 adverse events with dasa-
tor tyrosine kinase by imatinib, have been reported. tinib are hematologic and all cell lines can be affected. Some patients
may have bleeding from inhibition of platelet aggregation. Adverse
477
Other Effects of Imatinib events noted less frequently with dasatinib than imatinib include nau-
Imatinib has been found to cause regression of marrow fibrosis. One sea, vomiting, myalgia, rash, and fluid retention, including superficial
460
study found that the extent of marrow fibrosis in CML is not a prog- edema. Pleural effusions can be seen with dasatinib use. In one trial,
nostic factor with imatinib therapy, whereas another study observed 14 percent of patients had grade 1 or 2 pleural effusions at 24 months,
461
that although imatinib reverses marrow fibrosis in patients with CML, but grade 3 or 4 effusions occurred in only 2 patients. This toxicity did
it does not change the unfavorable prognosis associated with fibrosis. 462 not affect drug efficacy. Dasatinib may also increase the risk of pul-
Imatinib reverses exaggerated VEGF secretion in patients with monary arterial hypertension at any time, and this is an indication to
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CML, and it may reverse exaggerated marrow angiogenesis. It can discontinue dasatinib. Dasatinib may prolong the QTc interval, and
478
reduce marrow cellularity and normalize morphologic features regard- it should be used with caution in those who have long QT syndrome
less of cytogenetic response. BCR-ABL1–positive cells persist in patients or those taking drugs that may lengthen the QT interval. Hypophos-
474
despite prolonged treatment responses with imatinib. 465 phatemia was found in 7 percent of cases. 474
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