Page 1219 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 67 Chronic Myeloid Leukemia 1065

Newly Diagnosed Patients (ENESTnd) study compared two nilotinib patients with the T315I BCR-ABL mutation experienced a major
doses (400 mg twice daily and 300 mg twice daily) with imatinib cytogenetic response. However, 1 year after its accelerated approval
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400 mg daily. Both studies found the experimental arms (dasatinib by the US FDA, a high number of vascular occlusive events, both
and nilotinib) to be superior to imatinib in achieving the primary arterial and venous thromboembolic events, began to be reported,
endpoints (dasatinib: CCR by 12 months; nilotinib: MMR at 12 leading to the US FDA placing a partial clinical hold on the drug.
months). Patients treated with nilotinib had a significantly reduced The hold was lifted following dose-reduction recommendations, but
risk for progression. Based on these results, both nilotinib and use is currently restricted to patients with the T315I mutation or for
dasatinib were approved for front-line therapy of newly diagnosed whom no alternative TKI is available.
CP CML patients in the United States (US) in 2010. Omacetaxine mepesuccinate is a semisynthetic formulation of
Bosutinib, another dual Src/Abl kinase inhibitor, has also shown homoharringtonine, an alkaloid extracted from various Cephalotaxus
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potent activity against CML and was approved for the treatment of species. It has a distinct mechanism of action related to inhibition
CP, AP, and BC CML by the US Food and Drug Administration of protein synthesis—interfering with initial protein elongation—
(FDA) in 2012. Bosutinib overcomes the majority of imatinib- leading to decreased levels of proteins important for leukemia cell
resistant BCR-ABL mutations except the T315I and V299L muta- survival, including BCR-ABL MYC and MCL1. Omacetaxine is
tions. Bosutinib shows activity against certain mutations conferring approved for the treatment of adult patients with CP or AP CML
resistance to dasatinib (e.g., F317L) and nilotinib (e.g., F359V).The with resistance or intolerance to two or more TKIs. Of 111 CP or
recommended dose is 500 mg orally, taken once daily with food. The AP CML patients who received two or more prior TKIs, major
toxicity profile of Bosutinib differs from other approved TKIs in cytogenetic response was achieved in 18% of patients with CP, with
CML, possibly due to the minimal activity against platelet-derived median response duration of 12.5 months and major hematologic
growth factor receptor and KIT. The most common nonhematologi- response in 14% of patients with AP, with a median response duration
cal adverse events are gastrointestinal, including diarrhea, nausea, of 4.7 months. Omacetaxine is supplied as a single-use vial for par-
vomiting and abdominal pain, predominantly occurring within the enteral administration. Common adverse reactions included throm-
first 4 weeks of treatment and generally resolving spontaneously, and bocytopenia, anemia, neutropenia, diarrhea, nausea, fatigue, asthenia,
ALT elevations. Bosutinib provides an important additional treat- injection site reaction, pyrexia, and infection.
ment of CML patients previously treated with one or more TKIs, for
whom imatinib, nilotinib, and dasatinib are not appropriate options.
The choice of TKI in newly diagnosed patients remains open to Residual Disease in Patients Treated With Tyrosine
debate. Dasatinib and nilotinib are associated with faster and deeper Kinase Inhibitors
reduction in leukemia burden. On the other hand, no differences in
OS have been observed yet, although follow-up is required and long- Currently, reverse-transcriptase PCR (RT-PCR) is the most sensitive
term data from randomized clinical studies are needed to confirm the method for detecting low numbers of BCR-ABL transcripts in a
initial findings. Imatinib is less expensive, and there is longer experi- patient after apparently successful HCT. Most patients who have
ence with its use. A direct comparison between nilotinib and dasatinib been treated with imatinib and have responded well continue to
has not been performed. Since their overall efficacy appears to be demonstrate evidence of residual disease using sensitive PCR assays.
similar, the selection may be based primarily on side effect profile and Recent updates of clinical trials of imatinib in CP CML patients
convenience. Dasatinib treatment is associated with higher rates of indicate that an increasing proportion of patients appear to enter
myelosuppression and hemorrhage, and with pericardial and pleural molecular remission over time, including some patients achieving
effusion. In contrast, nilotinib can induce an increase in pancreatic a PCR-undetectable status. However, even patients with negative
enzymes, although radiographic/clinical pancreatitis is rarely noted. PCR (so-called CMR) may still have significant numbers of residual
Hyperglycemia and hyperbilirubinemia are observed in some malignant cells. Several groups have identified BCR-ABL–expressing
nilotinib-treated patients. More recent data suggest a risk for severe leukemia stem cells in patients with sustained undetectable molecular
peripheral arterial occlusive disease and other cardiovascular events, residual remission. Patients with undetectable minimal residual
including cerebral ischemia and myocardial infarction, in patients disease (MRD) after imatinib therapy continued to have BCR-ABL
receiving nilotinib. Skin rash is also a prominent side effect of nilo- rearrangement detectable at the genomic level, indicating persistence
tinib therapy, but this is usually moderate and/or resolves spontane- of residual leukemic cells not detected by RT-PCR. It is important
ously. Severe, uncontrolled diabetes and past pancreatitis may be to note that residual leukemic cells with leukemia-initiating capacity
considered as risk factors for nilotinib use, whereas patients with a have been shown to persist in CML patients in sustained molecular
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history of hypertension, asthma, pneumonia, gastrointestinal bleed- remission on imatinib. Together, these data suggest that imatinib
ing, chronic obstructive pulmonary disease, congestive heart failure, alone may not be capable of eradicating the leukemic cell clone,
vascular disease, autoimmune disorders, or concomitant aspirin use and at present, patients are recommended to continue medication
may be at increased risk for pleural and pericardial effusions, bleed- indefinitely, outside of investigational studies as described later.
ing, and infection with dasatinib. For the choice of the second- or
third-line TKI, mutational analyses, the occurrence of adverse events
related to treatment, and coexisting patient pathologies are important Discontinuation of Tyrosine Kinase
considerations. Inhibitor Treatment

Discontinuation of imatinib has emerged as an investigational
Drugs Targeting the T315I Mutation approach for patients with CP CML with undetectable MRD. A pilot
study of imatinib discontinuation in patients in CMR for 2 years
The fact that the T315I mutant is not responsive to either dasatinib indicated that half of the patients experienced molecular relapse
or nilotinib and that this mutant has been detected in some patients within 6 months of treatment discontinuation, but that the remain-
with acquired resistance to dasatinib and nilotinib underscores the ing patients did not develop molecular relapses with an extended
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need for drugs with T315I inhibitory activity. Ponatinib is a mul- follow-up of 4 years. These results were confirmed in the multicenter
titargeted kinase inhibitor active against all BCR-ABL mutants, STIM study, in which 40 out of 69 patients (61%) lost CMR within
including T315I. In a phase I study, more than 50% of patients in the first 6 months, and the probability of persistent CMR at 12
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CP, mostly patients in whom two or more TKIs had failed, attained months was 41%. Comparable results were reported in the Austra-
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CCR. The CCR rate was 92% in patients with the T315I mutation. lian TWISTER study, which used very similar entry criteria. At 24
Responses were less frequent and stable in patients with advanced months, the actuarial estimate of stable treatment-free remission was
disease. This was confirmed in a phase II study where 51% of patients 47.1%. Most relapses occurred within 6 months of stopping imatinib,
resistant to or intolerant of second-generation TKIs and 70% of and no relapses beyond 27 months were seen. The multicenter