Page 983 - Hematology_ Basic Principles and Practice ( PDFDrive )

866 Part VII Hematologic Malignancies

wild-type JAK2. Importantly, the majority of patients experienced a events is elevated, giving rise to the recommended use of an antico-
decrease in constitutional symptoms and improved exercise tolerance agulant regimen such as aspirin, low-molecular-weight heparin or
and performance status, as well as weight gain. In larger, randomized Coumadin. Nonetheless, efficacy is certainly seen clinically and has
trials, while clinical improvement was superior with ruxolitinib treat- been validated in SCID models of human myeloma. Data also point
ment, this agent was not effective in reversing histologic, cytogenetic, to its potential clinical efficacy in patients with solid tumors and
or molecular abnormalities in peripheral blood or BM, suggesting MDS. The approved dose of thalidomide for treatment of plasma cell
that ruxolitinib is not curative. Recent studies have also shown rux- myeloma is 200 mg PO given once daily. Dose reductions should be
olitinib to be effective in controlling symptoms, spleen size and considered in the presence of hematologic toxicity.
hematocrit in patients with polycythemia vera. Dosing of ruxolitinib
in myelofibrosis patients is based on platelet count, ranging from Lenalidomide
5 mg twice daily for patients with platelet counts lower than Lenalidomide was identified as an analog of thalidomide with more
50,000/µL to 20 mg twice daily if platelet counts are above potent immunomodulatory functions but fewer side effects.
200,000/µL; in patients with polycythemia vera the starting dose of Lenalidomide also has antiangiogenic properties, blocks IL-6 produc-
ruxolitinib is 10 mg twice daily. Rapid redevelopment of spleno- tion, and reduces NFκB and IκB levels. In addition, lenalidomide
megaly and symptom exacerbation can occur after abrupt interrup- induces caspase 8-mediated apoptosis and mitochondrial-mediated
tion or discontinuation of ruxolitinib. Common side effects of cell death. T-cell activation and increased natural killer (NK) activity
ruxolitinib include myelosuppression, primarily anemia, and throm- are observed, thus increasing the anticancer immune response.
bocytopenia requiring dose modifications; increased risk of infections Lenalidomide can cause a similar dose-dependent peripheral neu-
and herpes zoster; gastrointestinal symptoms (abdominal pain, diar- ropathy as thalidomide, and causes more significant myelosuppres-
rhea), fatigue and headache. sion, which can be dose limiting. The risk of thrombosis is also
increased and the administration of lenalidomide should be accom-
Other JAK2 Inhibitors panied by antithrombotic prophylaxis. Hypersensitivity rash occurs
Several other inhibitors with activity against JAK2 are under in up to 10% of patients. In trials of CLL and lymphoma, initial
investigation. treatment with lenalidomide can result in tumor flare, characterized
Pacritinib (SB1518) is a JAK2 inhibitor with activity against the by fever, rash and painful lymphadenopathy; lower initial doses
wild-type kinase as well as the JAKV617F-mutated kinase; it also should be considered in patients with high tumor burden and CLL.
inhibits fms-like tyrosine kinase 3 (FLT3). It achieves high rates of A variety of dosing schedules provides a flexible therapeutic approach
reduction in spleen volume. The tested dose is 400 mg daily. Recent and a high response rate in relapsed myeloma patients, with an ORR
studies confirm the activity of pacritinib in the treatment of MF, of 25% and median overall survival (OS) of 28 months. In 5q- MDS
resulting in improvements in hematologic, radiologic, and clinical patients, response in over 40% of patients was observed, indicating
symptom endpoints. The main side effects are gastrointestinal, pre- more based on the achievement of transfusion independence (see
dominantly diarrhea, nausea, vomiting, and abdominal pain, while Chapter 60). The activity of lenalidomide has been observed in
hematologic adverse events are modest. several lymphoid malignancies, with its current approval limited to
Momelotinib (CYT387) is an oral multikinase inhibitor affecting MCL that has relapsed after two lines of therapy. The approved
JAK1/2, TYK2, TBK1, PRKD1, ROCK2, PRKCN, MAPK8, and starting dose of lenalidomide is 25 mg PO once daily (days 1–21 of
CDK2/cyclin A. Early trials in myelofibrosis patients resulted in a 28-day cycle) for plasma cell myeloma and MCL. A dose of 10 mg
decreased splenomegaly and improvement in symptoms in the major- once daily is used in 5q- MDS patients.
ity of patients treated. Of note, more than one-third of patients with
improved splenomegaly had previously been treated with ruxolitinib. Pomalidomide
The most common side effects included myelosuppression, primarily Pomalidomide is a third-generation member of the immunomodula-
thrombocytopenia. Nonhematologic side effects included headache, tory drugs (IMiDs) class. In addition to its immunomodulatory and
QTc prolongation, neuropathy, and abnormal liver test results. The antiangiogenic activity, pomalidomide has direct activity against
maximum tolerated dose has been established at 300 mg/day given myeloma cells, affecting gene expression, and promoting apoptosis
continuously in 28-day cycles. and cell cycle arrest. Pomalidomide upregulates expression of p21 WAF
and downregulates interferon (IFN) regulatory factor 4. p21 WAF
inhibits CDK2, which in turn results in phosphorylation of the reti-
Immunomodulatory Agents noblastoma (Rb) protein and cell cycle arrest at G1. Apoptosis is also
induced via activation of caspase 8. In vitro studies showed that
Thalidomide and its related compounds provide effective oral immu- pomalidomide was active in cell lines resistant to thalidomide and
nomodulatory (see Chapter 86) therapy for patients with hematologic lenalidomide.
malignancies, in particular plasma cell dyscrasias and lymphoid malig- Phase I studies established that the maximum tolerated dose of
nancies. They have complex mechanisms of action. Further details on pomalidomide was 4 mg given PO on days 1–21 of 28-day cycles,
their therapeutic impact are found in Chapters 86 and 81–82. which corresponds to the currently approved starting dose. Results
of a phase II study combining pomalidomide with dexamethasone in
Thalidomide patients with relapsed myeloma showed an encouraging ORR of 63%
Experimental studies have identified that thalidomide reduces expres- (partial response [PR] or better), including 60% of patients who were
sion of the cellular inhibitor of apoptosis protein and potentiates pro- refractory to bortezomib and 40% of patients who were refractory to
apoptotic processes such as TNF-related apoptosis-inducing ligand lenalidomide. The most common severe adverse events are myelosup-
(TRAIL)/po2L. Thalidomide also reduces NFκB and IκB expression, pression (anemia, neutropenia, and thrombocytopenia), infections,
thereby reducing IL-6 expression. In addition, thalidomide decreases and fatigue. Venous thromboembolic events were observed in early-
vascular endothelial growth factor (VEGF) and reduces angiogenesis phase studies and subsequent trials have required thromboprophylaxis,
and vessel density in the bone marrow of patients with MM. The under which the rate of VTE with pomalidomide is less than 5%.
lack of a simple mechanism of action has been confusing because
it is unclear which, if any, biomarker is an appropriate correlate
for clinical success or toxicity. Thalidomide has been in clinical use Proteasome Inhibitors
for more than 50 years and has well-documented and sometimes
serious side effects, including severe birth defects, somnolence, axonal The 26S proteasome is the central proteolytic machinery of the highly
length-dependent peripheral neuropathy, orthostatic hypotension, conserved ubiquitin proteasome system. In eukaryotic cells, whereas
neutropenia, bradycardia and occasional heart block, and increased the lysosomal pathway degrades extracellular proteins imported into
viral load in HIV-positive patients. The risk of developing thrombotic the cell through endocytosis or pinocytosis, the proteasome controls