Page 1274 - Hematology_ Basic Principles and Practice ( PDFDrive )

1120 Part VII Hematologic Malignancies

TABLE Choice of Drugs for Treatment of Patients With treat ET patients. This formulation of IFN provides prolonged activ-
69.7 High-Risk Essential Thrombocythemia ity that permits once-weekly dosing. Normalization of blood counts
occurred after a median time of 2–3 months; 12% of patients dis-
Age (years) Treatment of Choice Second Line continued therapy because of inability to tolerate the drug, and 17%
<50 Interferon Anagrelide did not achieve normalization of their platelet counts. The majority
Hydroxyurea of side effects were WHO grade 1 or 2, although some encountered
grade 3 toxicity, primarily fatigue and flu-like symptoms. More
50–75 Hydroxyurea Interferon importantly, no thromboembolic or hemorrhagic complications
Anagrelide
occurred during the period of treatment, although 12 thrombotic
>75 Hydroxyurea Anagrelide events occurred in 42 patients (24%) in the 24 months before the
Busulfan institution of therapy. This form of IFN, however, appears to lead to
a similar frequency and severity of side effects during long-term use
as experienced with conventional IFN. Interestingly, the use of
another pegylated form of IFN (peg-IFNα-2a) in patients with PV
that aspirin therapy might be best avoided in patients being treated was able to decrease the percentage of mutated JAK2 allele in 24 out
10
with anagrelide. of 27 treated patients from a mean of 49% to a mean of 27%. The
The ANAHYDRET study was a prospective, randomized, non- use of this form of IFN appeared to be associated with fewer side
inferiority study comparing hydroxyurea to anagrelide treatment in effects than standard forms of IFN or peg-IFNα-2b. This form of
259 patients with treatment-naïve, high-risk ET (WHO diagnosis pegylated IFN has been used to treat approximately 40 patients with
6
confirmed). Anagrelide was determined to be noninferior to ET, with more than 75% of patients achieving a complete hemato-
hydroxyurea based on equivalent rates of thrombotic (arterial and logic remission. Almost 40% of patients with JAK2V617F-positive
venous) and hemorrhagic (major and minor) complications. A criti- ET had a reduction in their JAK2V617F allele burden, with occa-
cism of this study was the low rate of aspirin use in this study of sional patients no longer having detectable JAK2V617F, leading to
approximately 28% in both arms and the lack of date indicating rela- their being classified as having achieved a complete molecular remis-
tive rates of transformation to MF. sion. Although hematologic remissions were frequently achieved after
IFN-α has been used to treat the MPN associated thrombocytosis 3 months of therapy, the effects on JAK2V617F were observed after
since the 1990s. IFN-α acts by directly inhibiting megakaryocyte 6 months of treatment. Most patients were successfully treated with
colony formation and secondarily by inhibiting the expression of 45–90 µg/weekly, and 22% of patients ceased therapy because of
thrombopoietic-stimulating cytokines, such as GM-CSF, G-CSF, toxicity. Surprisingly, the hematologic and molecular responses persist
IL-3, and IL-11 and by stimulating the production of negative regula- for a number of months after discontinuation of therapy, suggesting
tors of megakaryocytopoiesis, such as IL-1ra (receptor agonist) that intermittent therapy may be an acceptable means of chronically
and macrophage inflammatory protein 1 (MIP-1a). IFN-α inhibits administering this drug. More recently, molecular responses in a
thrombopoiesis by suppressing thrombopoietin-induced phosphory- cohort of 31 CALR+ ET patients treated with peg-IFNα-2b were
lation of the JAK2 substrates, MPL and STAT5. Furthermore, IFN-α reported with a baseline allelic frequency of 41% reduced to 26%
also induces the production of suppressor of cytokine signalling-1, and two complete responses. Patients with additional subclonal muta-
which inhibits thrombopoietin-mediated cell proliferation. In a total tions (TET2, ASXL1, IDH2, and TP53) were less likely to achieve
of 212 patients treated with IFN-α in a total of 11 different clinical molecular responses. This is consistent with the finding that patients
trials, a response rate of approximately 90% was reported. Therapy harboring concurrent mutated JAK2 and TET2 can still have evidence
was administered to outpatients, most frequently at an initial dose of of persistent TET2, despite complete response of JAK2V617F after
3 million units daily, and usually produced a rapid decrease in peg-IFNα-2b therapy.
platelets within 2 months. The mean time to complete response with No data indicating whether IFN therapy delays or prevents the
a daily dose of 3 million units daily was about 3 months. IFN-α was evolution to MF are available. To gain a more comprehensive assess-
effective in patients who had received other chemotherapeutic agents ment of the clinical usefulness of IFN-α, a prospective clinical trial
and in patients resistant to conventional cytotoxic drugs. In the comparing IFN-α with hydroxyurea in patients with ET is underway
majority of patients, the IFN dose required to maintain a normal at numerous sites in North America and Europe. Until the results of
platelet count during maintenance therapy was lower than the induc- this trial are available, IFN-α or anagrelide should be considered as
tion dose. In one study, 61% of patients required 3 million units reasonable alternatives to hydroxyurea in a patient younger than 40
three times a week, 15% once a week, and 24% daily. In addition, years of age who has had a previous thrombotic episode (see Table
sustained remissions that persisted for 3–36 months were achieved 69.7), but which drug is the standard of care in so-called high-risk
with IFN-α therapy in 9–16% of patients. IFN-α is reported to be patients will require data emanating from the randomized trial. A
nonmutagenic and does not cross the placenta, making it a useful number of small-molecule inhibitors of JAK2 have been evaluated for
drug for the treatment of the symptomatic pregnant patient with ET. the treatment of ET patients. These agents reproducibly lower platelet
Reduction in platelet numbers with IFN results in a marked improve- counts, but the definition of the appropriate role of such agents in
ment in clinical symptoms. Toxicity, especially in older patients, the the treatment of ET patients will require their careful evaluation in
need for parenteral administration, and cost limit the usefulness of well-controlled clinical trials.
IFN-α. Side effects include flu-like symptoms during induction The use of platelet antiaggregating agents remains an important
therapy, such as fever, bone and muscle pain, fatigue, lethargy, and area of investigation. Patients with ET have an increased predisposi-
depression. Symptoms are frequently controlled with acetaminophen. tion to hemorrhage, which is likely potentiated by the use of drugs
Long-term administration of IFN-α can result in mild weight loss; that affect platelet function. Transient ischemic attacks and erythro-
alopecia; retinal abnormalities; rarely, a reversible form of sarcoidosis melalgia associated with ET respond rapidly to aspirin alone. In
and a reversible form of left-sided heart failure; and the development erythromelalgia, symptoms disappear for 2–4 days after administra-
of autoimmune conditions, including thyroiditis leading to hypothy- tion of a single dose of aspirin. Although these agents surely have a
roidism and autoimmune hemolytic anemia. Patients may develop role in the treatment of these specific complications, their use should
neutralizing antibodies to recombinant IFN, leading to a concomitant be pursued with extreme caution because of the increased risk of
rise in platelet numbers. Approximately 25% of IFN therapy-treated hemorrhage. Low-dose aspirin therapy has been uniformly recom-
ET patients discontinued therapy due to poor compliance or limiting mended for virtually all patients with ET independent of their risk
side effects. of developing a thrombotic event. These recommendations are
A semisynthetic protein polymer conjugate of IFN-α2b, pegylated somewhat surprising because they are based on two clinical trials of
IFN (peg-IFNα-2b), was anticipated to be superior to unmodified the effects of low-dose aspirin therapy in PV patients, and such a trial
IFN as related to its adverse event profile and efficacy when used to with aspirin has never been performed with a population of ET