Page 1296 - Hematology_ Basic Principles and Practice ( PDFDrive )

1142 Part VII Hematologic Malignancies

therapy and not embarked upon unless the patient is participating respond to androgen therapy. Danazol, a synthetic attenuated andro-
in a clinical trial. 11 gen, has also been useful in reducing the requirement for RBC
transfusion support and correction of thrombocytopenia in 20–40%
of treated patients in several series. Variables associated with response
Treatment of the Anemic Patient were lack of transfusion requirement and higher hemoglobin levels.
The experience with the use of rHuEPO in PMF has been reviewed
Anemia is a common problem in patients with PMF. It is usually by Cervantes and colleagues in a total of 51 patients, documenting
multifactorial in origin; contributing factors are folate deficiency, iron that 28 (55%) of these patients responded to rHuEPO treatment,
deficiency, ineffective erythropoiesis, erythroid hypoplasia, increased including 16 complete and 12 partial responses. Endogenous serum
clearance, and hemolysis. Patients with documented nutritional EPO levels inappropriately low for the degree of anemia is predictive
deficiencies should receive folate, iron supplementation, or both. of a favorable response to rHuEPO. Serum EPO levels below 125 U/L
Transfusion therapy with packed RBCs is clearly indicated in patients were found to be associated with a favorable response to rHuEPO
who are symptomatic from their anemia. Chronic transfusion therapy therapy. Responses can be associated with a limited enlargement of
is frequently required, and the clinician should try to attain a hemo- the spleen.
globin level at which symptoms resolve. Long-term transfusion The use of darbepoetin, a novel hyperglycosylated erythropoiesis-
therapy potentially may lead to the development of iron-overload stimulating protein, has been reported in 20 PMF patients. With an
syndrome. It remains unclear if iron chelation provides a meaningful initial weekly dose of 150 µg, increased to 300 µg, when no response
clinical benefit to patients with MF and the justification of the use was observed after 4–8 weeks, eight patients (40%) responded to
of this therapy has mostly been extrapolated from the MDS literature treatment, including six complete and two partial responses, and five
and case reports. Low-dose dexamethasone has been reported to be maintained their response after a median follow-up of 12 months
useful in the treatment of patients with transfusion-dependent PMF. (range: 4–22 months). The median time to response was 2 months.
Corticosteroids (e.g., prednisone 1 mg/kg/day taken orally) have Univariate analysis indicated that older age was the only factor associ-
also been successfully used for treatment of the hemolytic anemia ated with a favorable response to treatment (p < .006). None of the
associated with PMF. Other therapeutic options for PMF-associated patients with elevated serum EPO levels responded. Treatment was
hemolytic anemia can include therapy with intravenous immuno- usually well tolerated, and patients can be successfully switched from
globulins and recombinant human erythropoietin-α (rHuEPO). rHuEPO to darbepoetin.
Recently, retrospective analysis of single-agent prednisone therapy Multiple trials have explored the use of thalidomide in the treat-
for 30 intermediate-2 or high-risk PMF patients with anemia/ ment of anemia in PMF based on the drug’s antiangiogenic, immu-
thrombocytopenia was published. The initial dose was 0.5–1 mg/ nomodulatory, and antiinflammatory actions. A pooled analysis of
kg daily, with tapering to the minimum effective dose in responders. five small phase II studies indicated that 29% of patients with moder-
Twelve patients (40%) achieved an anemia response by IWG-MRT ate to severe anemia experience an increase in hemoglobin or reduc-
criteria. The median response duration was 12.3 months. Patients tion or elimination of blood transfusion requirements with
with constitutional symptoms or >2% circulating blasts had a lower thalidomide therapy at a standard dose of 200–800 mg/day. Never-
response rate. Median survival from the initiation of prednisone theless, most of the patients treated with these doses had adverse
therapy was significantly longer in anemia responders (5.0 years vs. effects that resulted in an attrition rate of greater than 50% after 3
1.5 years, p = .002). Additional information that supports the use months. Moreover, increases of WBC numbers or platelet counts
of corticosteroids for the treatment of MF-related anemia is derived were frequently reported to be associated with such serious adverse
from a prospective clinical trial that was constructed to evaluate the events as pericardial effusions secondary to myeloid metaplasia. Using
efficacy of the immunomodulatory agent, pomalidomide. This study a dose-escalation design and starting with a low dose of thalidomide
surprisingly revealed that prednisone alone can induce significant (50 mg/day), 31% of patients with transfusion-dependent anemia
responses in unselected MF patients with severe anemia. In this were reported to experience a response after treatment. A combina-
randomized study, the active control arm that included 21 patients tion of low-dose thalidomide (50 mg/day) with prednisone has been
consisted of prednisone (30 mg/day during the first 28-day cycle, reported to be a better-tolerated regimen and equally or more effec-
15 mg/day the second cycle, 15 mg every other day the third cycle) tive than standard-dose treatment. This regimen also had a significant
plus placebo (up to 12 cycles). Overall, four out of 16 (25%) patients effect on the degree of thrombocytopenia and resulted in a reduction
assigned to the control arm who completed three cycles of treatment in the degree of splenomegaly in almost 10% of the patients. These
achieved anemia response according to the IWG-MRT criteria. Three responses were frequently maintained after therapy was halted.
of the four responses were short-lived, lasting between 2.3 and 5.5 Higher doses of thalidomide were not more effective than lower
months. These data are similar to our own experience indicating doses. A prospective phase IIB, randomized, double-blind, multi-
that prednisone therapy can improve the anemia and thrombo- center trial compared therapy with 200–400 mg of thalidomide with
cytopenia associated with PMF even after the failure of standard placebo and documented that in the thalidomide group, only 10 out
therapies. of 26 patients completed 6 months of treatment and that no differ-
It is important to be aware that the hemolytic anemia in patients ence was observed between the thalidomide and placebo groups as
with PMF may also rarely be a consequence of a coexisting secondary regards to improvement of hemoglobin levels or reduction of the
form of paroxysmal nocturnal hemoglobinuria that can be responsive number of RBC transfusion required. In addition, experience with
to eculizumab therapy (see Chapter 32). Furthermore, patients with thalidomide therapy in a two-stage phase II dose-escalation trial in
PMF who receive multiple transfusions are candidates for developing 44 patients with advanced PMF has been reported. Starting at
delayed hemolytic transfusion reactions that occasionally may be 200 mg/day and increasing to 800 mg as tolerated, the median toler-
severe and persistent. The direct antiglobulin test result is usually ated dose was 400 mg for a median duration of 3 months, and 20%
positive in this setting. It is generally believed that additional transfu- of the patients experienced improvement in their degree of anemia
sions in these patients with delayed hemolytic transfusion reactions (21% became transfusion independent). A more potent thalidomide
should be avoided if possible. analog, lenalidomide, was evaluated in 68 symptomatic patients with
Anemia caused by erythroid cell hypoplasia as well as ineffective PMF at two institutions. Oral lenalidomide was administered at a
erythropoiesis in PMF may respond to anabolic steroids. A good dose of 10 mg/day if the platelet count was greater than 100,000/
3
response, as defined by a decrease or total avoidance of transfusion mm or at a dose of 5 mg/day if the platelet count was less than
3
therapy, occurs in about 20–40% of patients. A course of 3–6 months 100,000/mm for 3–4 months. The overall response rates were 22%
of androgen therapy is indicated to identify responsive patients, but for patients with anemia, 33% for patients with splenomegaly, and
the development of hepatic dysfunction or virilizing side effects may 50% for thrombocytopenia. Several patients normalized their hemo-
limit long-term androgen administration. Patients with associated globin levels or became RBC transfusion independent. The most
chromosomal abnormalities have been reported to be less likely to common associated toxicities were grade 3 and 4 neutropenia and