Page 1324 - Williams Hematology ( PDFDrive )

1298 Part X: Malignant Myeloid Diseases Chapter 84: Polycythemia Vera 1299

low risk associated with HU; analysis of 1638 PV patients enrolled in of IFN-induced autoimmune processes reflects the immunomodulatory
109
a prospective observational study and 1545 patients followed under activity of the drug, through which at least part of its antitumor activity
190
IWG-MRT did not find an increased incidence of leukemic or myelo- is mediated.
dysplastic transformation with HU treatment. A pegylated version of IFN-α (PEG-IFN-α) is better tolerated than
210
Unfortunately, despite its safety and effectiveness, approximately standard IFN-α and requires less frequent administration. A num-
10 percent of PV patients develop HU resistance or intolerance (i.e., ber of phase II trials have shown that PEG-IFN-α2a induces a complete
skin ulcers or gastrointestinal intolerance). 191–193 Resistance to HU is hematologic response in the vast majority of patients and a reduction
correlated with decreased survival and a higher rate of transformation in JAK2 V617F allelic burden in some. 211–215 Using JAK2 V617F as a molecular
191
to AML or MF. Effective alternative treatments are available. marker, a French group studied 40 PV patients treated with PEG-IFN-
Busulfan Busulfan is a useful second-line agent in patients whose α2a; 95 percent of evaluable patients had a complete hematologic remis-
disease is difficult to control or who have adverse reactions to HU. The sion, 90 percent had a decrease in JAK2 V617F allelic burden, and in 20
214
administration of busulfan is a convenient and effective means for treat- percent the JAK2 V617F allelic burden became undetectable. However,
ing PV. The marrow suppression produced by this drug is long-lasting the experience of the authors of this chapter is that we have not seen any
and, as a consequence, it can be given intermittently at a dose of 2 to true molecular remission in our therapy of more than 50 PV subjects
8 mg daily for a period not exceeding several weeks; blood counts con- and always detect a small level of JAK2 mutant in those considered in
tinue to fall for several weeks after drug administration is discontin- “molecular remission,” albeit it at times at levels of less than 0.2 percent.
ued. The disease is usually controlled for many months or even years. In Although IFN-α and PEG-IFN-α can be used as first-line therapy
193
one large study, the median first remission duration of busulfan-treated in PV, they are more often used as second-line treatments. PEG-IF-
194
patients was 4 years. The prolonged depression of marrow activity N-α is the drug of choice in pregnant patients (Chap. 8).
brought about by busulfan is its major advantage in the treatment of PV,
but it also poses a hazard of long-term pancytopenia. The incidence of Phlebotomy
transformation to leukemia may be increased with busulfan treatment. Often, the initial treatment for patients with uncomplicated PV is
In a large study of 1638 PV patients, busulfan was one of the agents phlebotomy. 31,197 Together with low-dose aspirin, it is at present the
which was associated with an increased rate of transformation to AML/ recommended therapy for low-risk PV cases.
MDS. When tested as a second-line therapy, busulfan robustly reduces When phlebotomy is instituted, the hemoglobin may be reduced
109
the JAK2 V617F allelic burden and causes a complete hematologic response to normal or near-normal values by the removal of 450 mL of blood at
in the majority of patients, 195,196 but also has a higher rate of transforma- one time every 2 to 4 days; smaller amounts should be removed from
tion to leukemia compared to first-line busulfan treatment. 196 patients who weigh less than 50 kg. Patients with impaired cardiovas-
32
Radioactive Phosphorus P therapy was one of the first effective cular function are better treated with smaller phlebotomies at more fre-
modes of treatment used in PV. Extensive investigations of the long-term quent intervals.
32
outcome of treatment with P have been documented. 76,197 Satisfactory Phlebotomy is an effective way by which to lower or normalize the
control of the disease usually can be achieved with initial doses of 2 to elevated blood viscosity of patients with PV. The reduction of hemoglo-
4 mCi. It is rarely used at present, but it may be the treatment of choice for bin levels may result in improvement of symptoms such as headaches
older patients and patients who may be difficult to follow. 198,199 or feeling of increased pressure. However, it does not reduce the leuko-
200
Interferon Since the pioneering work of Silver, IFN-α treat- cyte or platelet count, nor does it affect pruritus or gout. Iron deficiency
ment has been confirmed to result in clinical and hematologic remis- and resulting microcytosis are usual consequences of repeated phlebot-
sion in PV in more than a dozen studies. 201–204 Although these studies omies. An iron-deficient state may help control hemoglobin concen-
have many design similarities, they do not lend themselves to accurate tration in the long run, but it may increase platelet counts and fatigue
meta-analysis; various formulations of IFN were used (INF-α2a and in some patients. Judicious use of oral iron replacement therapy may
-α2b, PEG-INF-α2a, and -α2b, human leukocyte IFN), and heteroge- improve the fatigue associated with iron deficiency without significantly
neous criteria were employed to measure response. Nevertheless, it is increasing hematocrit.
clear that IFN-α effectively decreases many PV symptoms, including A randomized study 76,216 of a small number of PV patients compar-
pruritus, results in a hematologic response in approximately 80 percent ing phlebotomy to other treatments indicated that the survival of patients
of patients, and decreases the need for phlebotomies in approximately treated only with phlebotomy was slightly better than for patients treated
60 percent of patients. 201–204 with chlorambucil, and no worse than those given P. Patients undergo-
32
In addition to clinical and hematologic responses, administration ing phlebotomy did suffer more thrombotic episodes than patients treated
of IFN-α has led to a decrease in JAK2 V617F allelic burden 43,205,206 and with myelosuppressive therapy, although this risk seemed limited to the
conversion from clonal to polyclonal hematopoiesis in the small num- first 3 years of therapy. This documented increased risk of thrombosis
78
14
ber of patients studied thus far. Two comparisons of IFN-α2b and HU associated with phlebotomy was balanced by a lower incidence of acute
suggest that IFN-α2b may cause a greater molecular and hematologic leukemia late in the patient’s course. There was no correlation between
response than HU in PV patients. 207,208 platelet count and development of thrombotic complications. 216
However, IFN-α has significant adverse effects. Approximately The rationale for phlebotomy in patients with PV is based on a
25 percent of patients with PV and ET given IFN-α discontinue treat- widely quoted study that suggested the risk of thrombosis in PV was
217
ment, half of them within the first year. The hematologic toxicities proportional to the elevation in hematocrit. Although the underlying
include anemia, thrombocytopenia, and neutropenia. Other potential mechanisms causing thrombosis in PV are not fully understood, hema-
untoward effects of IFN-α include depression, mood changes, disabling tocrit is unlikely to be the only, or even a major risk factor, as the risk
fatigue, skin toxicity, hair loss, nausea, diarrhea, weight loss, liver func- of thrombosis is not elevated in patients with non-PV polycythemia or
tion abnormalities, and cardiac and neurologic toxicity. Immunologic in patients with secondary polycythemia caused by chronic exposure
218
abnormalities in the form of autoimmune processes (e.g., hypothyroid- to high altitude, Eisenmenger syndrome, or other cyanotic heart dis-
ism, autoimmune hemolytic anemia, polyarthritis, glomerulonephritis, eases. 219,220 In patients with Chuvash polycythemia, the risk of stroke is
connective tissue diseases, and asymptomatic antinuclear antibodies) similar regardless of whether hematocrit is controlled by phlebotomies
may be consequences of IFN therapy. Conceivably, the development (Chap. 37). Furthermore, the European Collaboration on Low-Dose
209

Kaushansky_chapter 84_p1291-1306.indd 1299 9/21/15 11:11 AM