Page 1325 - Williams Hematology ( PDFDrive )

1300 Part X: Malignant Myeloid Diseases Chapter 84: Polycythemia Vera 1301

Aspirin in the Polycythemia Vera study (ECLAP), which included Currently available JAK2 inhibitors target the catalytic site of the
1638 patients from 12 countries and 94 centers, found no difference in enzyme and therefore inhibit both wild-type and mutant forms of
thrombotic complications for patients with hematocrits in the range JAK2, as well as variable inhibition of JAK1, JAK3, and other kinases.
of 40 to 55 percent. An important attempt to clarify this issue was A number of JAK2 inhibitors are in clinical testing for PV, 236,237 includ-
221
a prospective study of the effect of hematocrit in PV patients, as eval- ing ruxolitinib (INCB018424), which is effective and FDA approved
uated by univariate analysis, which reported that patients treated with for use in patients with PMF. 238–241 Ruxolitinib is an oral JAK1/JAK2
222
phlebotomies had a decreased rate of thrombosis. However, patients inhibitor that has been shown effective in preclinical testing with PV
242
in the high-hematocrit group received less HU than those in the low- primary cultures and in phase II trials in HU-intolerant or refrac-
hematocrit group and had higher levels of leukocytes, both independent tory PV patients, 233,243,244 ruxolitinib effectively reduced PV-associated
correlates of thrombotic risk. 223 symptoms, such as night sweats, pruritus, and bone pain, within 4
weeks, decreased spleen size to nonpalpable in 44 percent of patients
Anagrelide by week 24, induced a complete hematologic response in 59 percent of
Anagrelide can be used in PV for thrombocytosis, as an adjunct to other patients, and reduced the JAK2 V617F allelic burden by equal to or greater
treatments. Among 113 PV patients with thrombocytosis, the adminis- than 50 percent within the first 3 years of treatment in 24 percent of
233
tration of anagrelide produced a platelet response in 85 cases (75 per- patients. Phase III trial showed that patients with HU-intolerant or
cent). The starting dose was 0.5 or 1.0 mg given four times daily, and refractory PV treated with ruxolitinib have a decreased requirement
224
a response was noted in most patients within 1 week. The average dose for phlebotomy, decreased spleen size, and improvement in other PV-
required to control the platelet count was 2.4 mg per day. Adverse events associated symptoms. 232
included headache, palpitations, diarrhea, and fluid retention, and were Despite the encouraging advances with JAK2 inhibitors, modula-
occasionally sufficiently severe to require discontinuation of the treat- tion of the JAK2 pathways may not be the sole optimal treatment for
225
ment. In patients with ET (Chap. 85), a randomized trial in the United PV and other MPNs. JAK2 V617F may not be the disease-initiating step in
Kingdom indicated superior results for HU plus aspirin compared to patients with MPNs, 37,245 and additional mutations may require specific
anagrelide plus aspirin for control of elevated platelet count, MF, and therapeutic targeting. Additionally, disease progression is characterized
hemorrhagic complications. However, a later randomized trial showed by clonal heterogeneity and genetic instability. Better characteriza-
246
26
a noninferiority of anagrelide to HU. 226 tion of the pathogenesis of PV is needed to facilitate further therapeutic
developments.
Symptomatic Therapy for Pruritus
Although some symptoms of PV can be controlled using phlebotomy, Epigenetic Modulation
control of pruritus is at times achieved using myelosuppression. Pruritus A high incidence of mutation in genes involved in epigenetic modifica-
is a major symptom of PV and, in some patients, it is nearly intolerable. tion in MPNs (i.e., TET2, DNMT3A, IDH1/2, PRC2, ASXL1) provides
When marrow proliferation is well controlled, pruritus becomes milder potential targets for therapy. 247,248 One currently used approach in cancer
or disappears entirely. Because bathing or showering usually intensifies treatment is interference of histone acetylation, as the acetylation status
the itching, the term aquagenic pruritus is often used. Some level of con- of histones can alter DNA-protein and protein-protein interactions.
249
trol of pruritus may be achieved by moisturization of the skin. Pho- The expression levels of histone deacetylases (HDAC) were found to be
tochemotherapy with psoralens and ultraviolet light can be helpful. altered in all three major MPNs, which has made HDAC inhibitors
227
250
Antihistamines are often given, but are usually not very effective, and a new therapy of interest in PV. For instance, Givinostat is an HDAC
neither is aspirin. Both IFN-α 229–231 and the JAK2 inhibitors provide a inhibitor which specifically inhibits the proliferation of JAK2 V617F -
228
generally effective treatment modality to alleviate pruritus. 232,233 positive cells compared to normal cells by inhibiting hematopoietic
251
transcription factors NFE2 and c-MYB. It has been found to reduce
252
Aspirin splenomegaly and pruritus in Phase II trials with PV patients. 253,254
Because thromboembolic episodes represent a major source of morbid-
ity and mortality in patients with polycythemia, aspirin is an important Summary of Therapeutic Approach
drug in the arsenal of treatment modalities for PV. The current approach for the management of the majority of PV patients
The results of early trials using 300 mg of aspirin daily showed an (i.e., high risk) who are not participating in a clinical trial is a combina-
increase in the incidence of bleeding without a measurable impact on tion of therapeutic and preventative approaches:
234
the incidence of thrombotic episodes. Subsequently, several studies
showed positive benefits of aspirin use in PV. A pilot-controlled trial 1. Myelosuppression with HU daily, both as initial therapy (1500 mg qd)
found that low-dose aspirin was well tolerated by PV patients and fully and long-term treatment (500 to 2000 mg qd), aiming to maintain
inhibited synthesis of the platelet aggregating compound thromboxane, neutrophil counts at low-normal levels. In addition, some patients
235
but not the endothelial cell protectant prostacyclin. An ECLAP study will require the use of phlebotomies and/or anagrelide to maintain
showed that daily low-dose aspirin decreased arterial and venous throm- hemoglobin and platelet levels in normal ranges. Myelosuppression
boses, albeit incompletely. Because thrombotic complications were not can also be achieved by other agents such as IFN-α or PEG-IFN-α.
75
completely prevented, this study suggested that only a minor fraction PEG-IFN-α is better tolerated than IFN-α and is the most effective
of thromboses are attributable to platelets, and additional pathogenetic therapy, but it is not as well tolerated as HU.
pathways in PV should be investigated. The increased risk of bleeding 2. Low-dose aspirin at 80 mg qd (or 100 mg outside of North America)
with high platelet counts and associated acquired von Willebrand disease is given to all patients without history of major bleeding or gastric
is discussed in the preceding section entitled Platelets; aspirin should not intolerance, or those with platelets over 1000 to 1500 × 10 /L.
9
be used when the platelet count exceeds 1000 to 1500 × 10 /L. 3. Medication to control pruritus and gout may be added if required.
9
4. Judicious use of phlebotomies in patients with hematocrits greater
JAK2 Inhibitors than 45 to 55 percent and in patients who find phlebotomy relieves
JAK2 inhibitors represent a promising new therapeutic avenue that their symptoms, such as headaches, difficulty concentrating, and
236
arose with the discovery of abnormal JAK-STAT signaling in MPNs. fatigue.

Kaushansky_chapter 84_p1291-1306.indd 1300 9/21/15 11:11 AM