Page 1479 - Williams Hematology ( PDFDrive )

1454 Part X: Malignant Myeloid Diseases Chapter 89: Chronic Myelogenous Leukemia and Related Disorders 1455

Dasatinib is metabolized primarily by hepatic cytochrome P450 was 70 percent for bosutinib and 63 percent for imatinib. 491,492 Results
(CYP) 3A4 enzymes, so inducers of this enzyme may decrease the effec- from followup of MMR rates, transformation rates, and durability of
tive dose, and inhibitors may increase the effective dose. Increases or remission are not yet available.
decreases in administered dose may be needed to compensate for these
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effects. Antacids can also reduce dasatinib effects. Lymphocytosis Summary of Tyrosine Kinase Inhibitor Selection for Initial
from the clonal expansion of NK/T cells has occurred during dasatinib Therapy of Chronic Phase Chronic Myelogenous Leukemia
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treatment. In a population of dasatinib-treated patients with large The goal of initial TKI therapy is to achieve a CCyR within 12 months
granular lymphocyte expansion, 90 percent had T-cell receptor delta or no later than 18 months of therapy, and to prevent progression to
481
rearrangements, the functional significance of which is unknown. the accelerated or blast phase. How best to achieve these goals remains
Lymph node follicular hyperplasia has been noted on dasatinib ther- controversial. Hence, the National Comprehensive Cancer Network
482
apy. Unlike the case with imatinib, dasatinib cellular uptake is not (NCCN) guidelines list imatinib, nilotinib, and dasatinib as all being
affected by octamer-binding protein-1 (OCT-1) activity, which is a sub- acceptable TKIs for initial treatment of CML. Many clinicians would
492
strate of the efflux proteins, ABCB1 and ABCG2. Resistance to dasat- choose a second-generation TKI, given the rapidity and depth of
inib is often found with point mutations in ABL1 at residue 315 or 317. response and the lower rates of transformation to advanced phases of
Nilotinib Unlike dasatinib, nilotinib is a selective, orally bioavail- the disease, but others use imatinib because of the lack of proof of pro-
able, ATP-competitive inhibitor of BCR-ABL1 which is 20 to 50 times longation of survival with nilotinib or dasatinib. In those with interme-
483
more potent than imatinib in vitro. Like imatinib, it does not induce diate- or high-risk disease as assessed by the Sokal and Hasford models
apoptosis in CD34+ CML cells. As with dasatinib, nilotinib was first (see “Course and Prognosis” below for details of these scores), nilotinib
484
tested as initial therapy in phase II trials, which were followed by a or dasatinib may be preferred over imatinib to achieve rapid, better
485
randomized phase III trial. In one phase II trial, 51 patients received responses—the “hit hard, hit early” approach. Thus, until survival
493
nilotinib 400 mg, twice a day, and 98 percent entered CCyR and 76 per- data are available, any one of the three approved TKIs may be used for
486
cent had a MMR by 6 months. The phase III trial compared nilotinib, initial therapy. Choice of agent may be dependent upon cost consider-
300 mg twice daily, 400 mg twice daily, and imatinib 400 mg daily. At ations, ease of administration, patient risk scores or perceived risk,
487
494
12 months, the MMR which had been chosen as the primary end point, and the drug’s side-effect profile (see Table 89–2).
was 44 percent (nilotinib 300 mg dose), 43 percent (nilotinib 400 mg
dose), and 22 percent (imatinib 400 mg daily). The CCyR rates were Defining a Response to Tyrosine Kinase Inhibitors
15 percent higher with nilotinib than imatinib. The rate of progression Table 89–3 contains definitions of hematologic, cytogenetic, and molec-
to accelerated or blast phase was 4 percent at 1 year with imatinib and ular responses. The guidelines for periodic monitoring patients who are
less than 1 percent with nilotinib. These improvements were observed in chronic phase and receiving TKI therapy are shown in Table 89–4.
in each prognostic group based on Sokal risk groups. The patients using The median BCR-ABL1 levels for imatinib-treated patients can decrease
either 300 or 400 mg doses had minimal differences, so in 2010, nilotinib over at least 5 years. Table 89–5 lists the milestones at 3, 6, 12, and
495
was approved at a dose of 300 mg twice daily for initial CML therapy. At 18 months expected of patients as indicators of an appropriate response
4 years of followup, more patients using either dose of nilotinib achieved in patients treated initially with a TKI. There is variation in an indi-
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a MMR than those using imatinib (73 and 70 percent vs. 53 percent). vidual patient’s time to maximal response. Consequently, if a patient has
488
The rates of progression to accelerated and blast phase were also lower not met those precise milestones but shows a continued decrease in the
for nilotinib than imatinib. The 4-year freedom-from-progression and proportion of Ph chromosome–positive cells on cytogenetic examina-
overall-survival rates were not different between the two groups. MMR tion of marrow, or if in a CCyR, a continued decrease in the level of
rates at 3 years were higher for those patients using nilotinib, 300 mg, the PCR signal for BCR-ABL1 and is near the benchmark, the treatment
twice per day, in the three risk groups of Sokal (low risk, 79 percent; can be continued. Only (1) failure to meet the benchmarks at 3, 6, or 12
intermediate risk, 76 percent; and high risk, 52 percent progression as months or (2) loss of response as defined as loss of a CHR or CCyR, (3)
compared to those using imatinib (65, 55, and 30 percent progression, development of new cytogenetic abnormalities, (4) acquisition of a BCR-
respectively). There was a reduced incidence of BCR-ABL1 muta- ABL1 mutation, or (5) an increase in the BCR-ABL1/ABL1 ratio of 1-log
488
tions in in patients using nilotinib compared to those using imatinib. or more on serial RT-PCR testing or into the range associated with reap-
Nilotinib use led to fewer (less than half as many) treatment-emergent pearance of the Ph chromosome on G-banding should generate a change
BCR-ABL1 mutations than did imatinib treatment, and to reduced rates in treatment to limit the risk of progression of the disease. Because of
of progression to accelerated phase and blast crisis in patients with these the variability in PCR testing, those changes should be confirmed within
mutations. 489 1 month. Patients who have 100 percent Ph chromosome–positive cells
Toxicity of Nilotinib Nilotinib is rarely associated with edema after 6 months of therapy have a minimal chance of achieving a MCyR
or muscle cramps. Grades 3 and 4 cytopenias were seen in 29 percent or CCyR and may be offered allogeneic stem cell transplantation, if
487
of cases in one trial. Grade 3 or 4 elevations in lipase, bilirubin, and applicable. 417,496
hyperglycemia were observed in 17, 8, and 12 percent of patients, and Achieving a cytogenetic response is associated with progres-
hypophosphatemia was seen in 16 percent. QTc prolongation can occur, sion-free survival in patients treated with imatinib and is an impor-
so one should monitor the electrocardiogram (EKG) readings for 7 days tant goal of therapy (97 percent in those with a CCyR vs. 81 percent
483
after starting therapy and with dose changes. Electrolyte abnormali- in those without a MCyR). At 5 years of followup, of those patients
497
ties should be corrected at outset of treatment. Nilotinib may be associ- who achieved CCyR on imatinib in the IRIS study, only 3 percent
ated with an increased risk of peripheral vascular disease, which may be had progressed to accelerated or blast phase during treatment. A
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490
arterial or venous. If thrombosis occurs, it should no longer be used CCyR at 1 year may be the major predictor for overall survival and
for therapy. progression-free survival. In patients in chronic phase treated with
498
Bosutinib and Ponatinib These TKIs are not approved for use imatinib, nilotinib, or dasatinib, early responses (at 3 months) in BCR-
in initial therapy. In the one trial, which compared efficacy for bosu- ABL1 transcript reduction or decrease of Ph chromosome frequency
tinib, 500 mg once daily, with imatinib, 400 mg daily in newly diagnosed predicted for better outcomes as measured by event-free or overall
chronic phase patients, the primary end point of CCyR at 12 months survival. For example, patients with less than 10 percent BCR-ABL1

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