NcXHF

JEAN-JACQUES KILADJIAN
in reducing platelet counts in both studies. In the PT-1 study,
an excess of arterial thrombosis was observed in the
anagrelide arm compared with HU. 34 However, in the
ANAHYDRET study that included patients with ET who
were strictly diagnosed using World Health Organization
criteria (including a bone marrow biopsy in all patients to
rule out early phases of myelofıbrosis), study equivalence was
reported. 35 Based on these results, HU and low-dose aspirin
combined is often the recommended fırst-line therapy for
high-risk patients with ET, 1 but anagrelide also may be appropriate
in specifıc subgroups of patients. Of note, in the absence
of ischemic symptoms or vascular complication, platelet reduction
should be progressive over a few weeks with increasing
doses of cytoreductive drugs to avoid the occurence of
thrombocytopenia or leukopenia.
The role of IFN-alfa therapy in ET needs to be clarifıed,
although many small, phase II studies have shown that this
drug also was very effıcient to control thrombocytosis. 26 In
addition, it has been shown that IFN-alfa was able to induce
molecular responses by reducing the mutant allele burden in
patients harboring mutations in JAK2 23 or in CALR 36 genes.
Whenever possible, patients with ET should be enrolled in
randomized studies evaluating HU compared with IFN, like
the ongoing MPD-RC 112 study (NCT01259856). Anagrelide
may be used as second-line therapy for patients who are resistant
to or intolerant of HU. IFN-alfa and busulfan also are
possible options in this setting. The use of cytotoxic agents, in
the youngest patients or, especially, in combination should
be avoided when possible, and IFN-alfa or anagrelide could
be the best options in these situations.
TREATMENT OF MYELOFIBROSIS
Because there is no curative therapy other than ASCT for myelofıbrosis,
treatment basically is palliative and usually is
guided by the principal disease manifestation.
Anemia
Of note, no drug has approval for this particular indication. A
hemoglobin of less than 10 g/dL, which is an adverse prognostic
factor, usually prompts consideration of treatment, although
this threshold obviously is subject to adaptations depending on
age and comorbidities. One option is the use of erythropoiesisstimulating
agents, which have been reported to improve anemia
in 25% to 50% of patients. 37,38 Patients who have low
endogenous erythropoietin levels (less than 125 mU/mL) may
be the best candidates for this therapy, whereas patients who
have major splenomegaly or transfusion dependence are unlikely
to experience clinically relevant improvement. Androgens
also have reportedly improved anemia in a similar proportion of
patients. In this class of drugs, danazol is the treatment of choice,
inducing similar results with less toxicity at the recommended
dose of 400 mg to 600 mg daily maintained for at least 6 months,
then progressively reduced to the minimum necessary for maintenance.
Immunomodulating agents also may be useful in managing
MF-related anemia. Low-dose thalidomide or low-dose
lenalidomide, combined for the induction treatment with prednisone,
provide a 20% to 30% response. 39,40 Of note, lenalidomide
as a single agent is the treatment of choice for patients with
MF who have a 5q deletion. 41 Corticosteroids alone sometimes
may be helpful and provide a modest benefıt for patients resistant
to the above-mentioned therapies, especially if a hemolytic
part can be demonstrated. Last, splenectomy can be useful in
patients who have transfusion-dependent anemia that is refractory
to any therapy, 42 but it needs careful evaluation because of
the risks of complication.
Splenomegaly and Other Sites of Extramedullary
Hematopoiesis
Usually, treatment of splenomegaly is not necessary per se, at
least until the onset of associated symptoms. HU used to be
the fırst-line therapy for symptomatic splenomegaly, and approximately
40% of patients experienced a reduction in
spleen size. 43 However, HU effıcacy is usually modest (spleen
size diminishing only of a few centimeters) and not durable;
published experience suggests that the majority of patients
need an alternative treatment after a median time of 12 months.
HU currently is clearly superseded by JAK inhibitors in this indication.
Splenectomy is sometimes required in patients who
have large and painful splenomegaly that is refractory to medical
therapy. 42 Splenectomy requires an experienced surgical team
and critical care support to minimize the risks associated with
the procedure, because mortality and morbidity rates of 5% to
10% and 25%, respectively, have been reported in a large, singlecenter
experience. 42 Splenic irradiation is another alternative
treatment of refractory and symptomatic splenomegaly. 44 However,
this treatment should be used with caution (fractionated,
low dose) because of a high risk of severe cytopenias. In addition,
the benefıt is only transient. In contrast, low-dose radiation is
the therapy of choice for symptomatic extramedullary hematopoiesis
in sites other than the spleen and liver (e.g., skin, central
nervous system). 45
The Role of JAK Inhibitors
This new class of drugs clearly has changed our management of
MF for a signifıcant proportion of patients and has provided unanticipated
benefıts. These drugs were designed to target the
dysregulated JAK-STAT signaling pathway, a typical feature of
patients with MPN independent of the presence of the JAK2
V617F mutation. Better knowledge of the complexity of the mutational
landscape of MPNs clearly demonstrates now that the
story of these drugs will not be similar to that of tyrosine kinase
inhibitors in chronic myeloid leukemia. In addition, currently
available JAK2 inhibitors are not selective for the mutant form
and, thus, inhibit wild-type JAK2 signaling as well (explaining
the on-target hematologic toxicity usually observed with these
agents). To date, only ruxolitinib, the fırst-in-class oral JAK1/
JAK2 inhibitor, has been approved for MF treatment. Two independent,
phase III studies have shown signifıcant effıcacy of
ruxolitinib to reduce splenomegaly and improve symptoms
compared with placebo (COMFORT-1 study) 4 or the best available
therapy (COMFORT-2 study). 3 These benefıts usually occur
within a few days after ruxolitinib initiation and are durable
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