Page 366 - Williams Hematology ( PDFDrive )

340 Part V: Therapeutic Principles Chapter 22: Pharmacology and Toxicity of Antineoplastic Drugs 341

This observation was made particularly in patients with Philadelphia receiving other TKIs. Other nonhematologic adverse effects include
chromosome–positive ALL or with CML progressing to blastic cri- hypophosphatemia (primarily dasatinib and nilotinib), muscle pain,
sis 252,253 and strongly supports the hypothesis that drug-resistant cells pancreatitis, and weight gain (particularly imatinib). All agents can
arise through spontaneous mutation, and are further selected by drug induce neutropenia, anemia and thrombocytopenia that can require
exposure. transfusion support, dose reduction, or discontinuation. Most nonhe-
The site of the resistance mutation has predictive and prognostic matologic adverse reactions are self-limited and respond to dose adjust-
implications. Among CML patients, mutations are detectable in some ments. After the adverse events have resolved, many times the drug may
patients receiving imatinib, including one-third of those undergo- be retitrated back to initial dosing. Ponatinib poses a clearly increased
ing treatment in the accelerated phase and in late (longer than 4 years risk of arterial thrombosis, and should be used with caution in patients
252
from diagnosis) chronic phase CML. Most patients with mutations with a history of myocardial infarction, angina, stroke, or peripheral
demonstrate clinical resistance at the time a mutation is detected, or arterial disease.
shortly thereafter. Prior to the development of second generation TKIs,
mutations involving the phosphate binding loop were associated with
rapid disease progression and death within a median of 4.5 months. The JANUS KINASE INHIBITORS
availability of highly active second- and third-generation TKIs that are
effective against all known kinase mutations resulted in improved dis- Myeloproliferative neoplasms (MPNs) are a group of heterogeneous
ease control and overall survival in these patients. 246,254–256 As first-line clonal hematopoietic stem cell disorders that include CML and “BCR-
agents, nilotinib and dasatinib are similarly effective, demonstrating ABL–negative” MPNs polycythemia vera (PV), essential thrombo-
264
high rates of progression free survival and overall survival. The choice of cythemia (ET), and primary myelofibrosis (PMF). A phenotypic
a second-line TKI depends on disease and patient characteristics as well characteristic of these disease is the accumulation of mature-appearing
as the side-effect profile of the different agents. For example, currently, myeloid cells. The majority of patients with BCR-ABL–negative MPNs
there is no alternative to ponatinib for CML with T315I mutation. carry a mutation in the Janus-type tyrosine kinase (JAK) gene, the most
.
In patients with targeted CHF or pleural effusions, dasatinib should common being JAK V617F 265–267 Family members of the JAKs include
be avoided given high rate of pleural effusions in up to 35 percent of JAK1 to JAK3 and TYK. Physiologically, JAK are necessary for intra-
patients. These patients should be given nilotinib or bosutinib instead. cellular signal transduction of receptors that have no intrinsic tyrosine
In patients with severe diabetes or a history of pancreatitis, one should kinase activity, such as receptors for erythropoietin (EPO), thrombo-
avoid nilotinib and choose another second-generation TKI when pos- poietin (TPO), and granulocyte-macrophage colony-stimulating factor
268
sible. Patients who fail two or more TKIs, including those with T315I (GM-CSF). Upon ligand binding to the receptor, JAK autophospho-
mutation, may also respond to omacetaxine mepesuccinate, a cytotoxic rylation leads to binding of signal transducer and activator of transcrip-
natural product that was FDA approved. 233 tion (STAT), which dimerizes with another STAT protein, translocates
In addition to kinase mutation, amplification of the wild-type into the nucleus, and promotes transcription of STAT-responsive genes,
kinase gene, leading to overexpression of the enzyme, has been iden- which are involved in the control of cell proliferation, apoptosis, and
265
tified in tumor samples from a few patients with resistance to treat- cell differentiation. The substitution mutation JAK2 V617F is the most
ment. The MDR gene, which codes for a drug efflux protein, confers common gain-of-function alteration and occurs in 65 to 97 percent of
257
258
resistance to imatinib experimentally ; thus far this mechanism has cases in PV, 23 to 57 percent of cases in ET, and 34 to 57 percent of cases
not been implicated in clinical resistance. In addition to efflux mecha- in PMF. 261–263 Expression of this mutation results in ligand independent
nisms, influx mechanisms may also play an important role. Recent stud- growth or increased sensitivity to the cytokine/growth factor.
ies indicate that imatinib but not nilotinib or dasatinib is taken into cells In 2011 the FDA approved the first specific JAK inhibitor ruxoli-
via the organic cation transporter-1 (OCT1) and that downregulation of tinib (Jakafi) for the treatment of PMF, PV, and ET. This approval was
this pathway may confer resistance. 259 the consequence of two phase III trials: Controlled Myelofibrosis Study
Not all resistance is explained by kinase amplification or muta- with Oral JAK Inhibitor Treatment (COMFORT)-I trial that investi-
tion, or by pharmacokinetic factors. There is a growing awareness of the gated the activity of ruxolitinib (15 mg or 20 mg orally twice daily) ver-
appearance of mutant Philadelphia chromosome–negative clones carry- sus placebo in 309 patients with PMF, PV, or ET, and the COMFORT-II
ing the karyotype of myelodysplastic cells in patients receiving imatinib trial that assessed ruxolitinib versus best available therapy in 219
for CML, and a few cases of progression to MDS and AML have been patients with PMF, PV, or ET. 266,267 In the COMFORT-I trial, ruxolitinib
reported. 260,261 Ongoing research into novel agents for resistant CML produced greater than 35 percent spleen volume reduction (primary
includes evaluation of HDAC inhibitors, heat shock protein inhibitors, outcome) in 42 percent of patients at 24 weeks, improved symptom
and targeted therapies of alternative pathways. control, and overall survival compared to the placebo group. In the
COMFORT-II trial 28 percent versus 0 percent of patients had greater
than 35 percent spleen volume reduction, as well as superior reduction
Adverse Effects of disease-related symptoms, functionality and quality of life with mod-
Imatinib, dasatinib, nilotinib, and bosutinib have modest toxicity. All est toxicities compared to best available treatment (mostly hydroxyurea
cause low levels of gastrointestinal distress, including nausea and vom- and glucocorticoids).
iting. Significant diarrhea occurs more frequently with use of imatinib
and bosutinib. All can promote fluid retention resulting in peripheral
edema and pleural effusions, with dasatinib causing significantly more Mechanism of Action
edema than the other drugs of this class. 262,263 Although all agents cause Ruxolitinib inhibits all JAK kinases independent of their mutational sta-
rashes, imatinib and bosutinib tend to promote more-severe (grades III/ tus and to similar degree independent from the disease subtype. There
IV) rashes in up to one-third of patients. Mild elevation of transami- is variable activity against JAK1 (IC = 1 nM), JAK2 (IC = 7.2 nM),
50
50
nases is seen with all BCR-ABL inhibitors, but more-severe elevation TYK2 (IC = 9.3 nM), and JAK3 (IC = 98 nM), respectively. Molecular
50
50
with bosutinib. Bilirubinemia is a rather uncommon adverse effect but dynamics simulations suggest that ruxolitinib targets the ATP-binding
268
it is frequently observed with use of nilotinib. Dasatinib and nilotinib site of the kinase in its active conformation. Administration of ruxoli-
cause a prolongation of the QT interval that is not seen in patients tinib results in decreased expression of STAT responsive genes.

Kaushansky_chapter 22_p0313-0352.indd 341 9/18/15 10:26 PM