Page 656 - Hematology_ Basic Principles and Practice ( PDFDrive )

558 Part V Red Blood Cells

20–30 mg/kg/d, induced decreases in LIC by biopsy comparable gastrointestinal side effects. Postmarketing safety studies are currently
with that achieved with deferoxamine. Patients with LICs greater under way.
than 7 mg/g dry weight receiving deferasirox at 20–30 mg/kg/d had
a mean decrease of 5.3 mg/g dry weight that did not differ signifi- Specific Complications and Their Management
cantly from a mean decrease of 4.3 mg/g dry weight in patients
receiving 35 mg/kg/d or more deferoxamine. Changes in serum fer-
ritin were dose dependent in both treatments, paralleling trends in Skeletal Changes
240
liver iron content. Doses of 5 and 10 mg/kg/d of deferasirox were
unlikely to achieve negative iron balance and did not maintain or Low Bone Mass
reduce absolute LIC and serum ferritin levels increased at these lower With improved survival in patients with thalassemia major, the
doses. The rate of transfusional iron loading may also influence the problem of osteoporosis has assumed greater importance. Approxi-
241
effectiveness of deferasirox in controlling LIC. Using a dose of mately 50% to 80% thalassemia patients have an osteoporosis–
20–30 mg/kg/d of deferasirox to reduce LIC has been demonstrated osteopenia syndrome. 251,252 Vertebral fractures are associated with
in several additional studies. 241–243 osteoporosis and cause significant morbidity in this population. Poor
Higher doses of deferasirox at 30–50 mg/kg/d have been demon- bone health begins in childhood and progresses in young adulthood.
strated to significantly improve cardiac T2* iron deposition over 2 Lumbar and thoracic vertebrae fractures are present in over 30% of
years of treatment in two groups of thalassemia patients with normal thalassemia patients over the age of 30 years. 253,254 The widespread
ventricular function but with either moderate to mild siderosis (T2* prevalence of osteoporosis in patients with thalassemia major was first
255
244
= 10 to <20 ms) or severe (T2* >5 to <10 ms) cardiac siderosis. observed across all ages in 1995. Subsequently, others reported a
These benefits appear progressive over 5 years with continuing high frequency of abnormal Z scores in pediatric, adolescent, and
245
improvement of cardiac T2* and LIC. Furthermore, in the adult patients. Abnormal bone mineral density has been reported in
CORDELIA trial, deferasirox appears efficacious and tolerable over pediatric and adolescent patients with thalassemia major. 256–258 The
time when compared with deferoxamine at reducing LIC and cardiac Thalassemia Clinical Research Network has identified the overall
246
siderosis. Failure of T2* cardiac siderosis to respond to deferasirox fracture prevalence of 12% in a contemporary sample of 702 patients
247
has been predicted by higher baseline LICs and ferritin levels. with α- and β-thalassemia. The fractures occurred more frequently
Deferasirox has also been shown to prevent cardiac iron accumulation in thalassemia major (17%) and intermedia (12%) compared with
in thalassemia patients without evidence of cardiac siderosis as well β-E (7%) and α-thalassemia (2%). Facture prevalence increased with
259
248
as improvement in left ventricular function. Deferasirox in combi- age and with sex hormone replacement therapy. More recently an
nation with deferiprone, an all-oral combination, was as safe as observational study by the Thalassemia Clinical Research Network
deferoxamine-deferiprone at reducing iron in severely overloaded has demonstrated a high prevalence of low bone mass across all the
young β-thalassemia major patients, and superior in patient thalassemia syndromes, including β-thalassemia major, intermedia,
satisfaction. 249 β-E, Hb H, H-Constant Spring, and homozygous α-thalassemia,
Deferasirox was generally well tolerated in these clinical trials. which progresses with aging. In addition, increased serum and
Mild gastrointestinal complaints and skin rashes were the most urine markers of bone turnover have been described in thalassemia
common adverse events. Discontinuation of deferasirox was rarely patients with osteoporosis, which correlate with low dual-energy
required, but abdominal discomfort occurred in 14% of patients, X-ray absorptiometry scores and improve with bisphosphonate
260
12% with diarrhea, 10% nausea, and 9% vomiting. Mild increases therapy. It remains unclear if different chelation therapies and
261
in serum creatinine occurred in 38% of patients, and a small number transfusions can alter the progression of osteoporosis. Zinc supple-
exceeded the upper limits of normal; intermittent proteinuria was mentation may also improve bone density in younger patients with
also observed in 19% of patients. Duplicate serum creatinine level thalassemia. 262
should be assessed before initiating therapy. Close monthly monitor- Skeletal abnormalities (Fig. 40.9) are less common in patients
ing of serum creatinine needs to be maintained because of nephropa- receiving regular RBC transfusions but may still occur as a result
263
thy in animal studies and cases of acute renal failure that were of partially unchecked IE and expansion of the erythroid BM.
reported after postmarketing use of deferasirox. Severe renal compli- These cause widening of the BM space and thinning of the cortex,
cations may occur in patients with preexisting renal disease. Dose with consequent osteoporosis. 255,264 Changes in the skull and facial
reduction, interruption, or discontinuation should be considered for bones, including expansion of the frontal bone with prominent
elevations in serum creatinine. More recent trial data suggests that frontal bossing, may occur before the initiation of transfusion
deferasirox-induced changes in creatinine and renal hemodynamics therapy. Radiographs reveal the diploic spaces to be widened. At
are usually mild and reversible for up to 2 years of treatment without first, the skull has a granular appearance, but later perpendicular
250
progression over time. Elevations in serum transaminases also bony trabeculae appear, giving the classic “hair on end” or “crewcut”
occurred in a small number of patients (6%). Rare reports of fulmi- appearance. Marked overgrowth of the maxilla results in severe
nant hepatic liver failure have resulted in the recommendation to malocclusion, jumbling of the upper incisors, and prominence of
265
obtain liver function tests every 2 weeks for 1 month after starting the molar eminences. These bone changes produce the classic
therapy and then monthly thereafter with interruptions or discon- thalassemic facies. Additional skeletal changes are observed in the
tinuations of deferasirox if unexplained or progressive transaminase metacarpals, metatarsals, and phalanges, where expanded medullary
increases occur. Skin rashes also occurred in 15% of patients usually cavities produce a rectangular and then a convex shape (see Fig.
within the first 2 weeks of treatment. The maculopapular eruptions 40.9). Irregular fusion of the epiphyses of the proximal humerus
often resolved spontaneously, but severe rashes may require interrup- results in characteristic shortening of the upper arms. 266,267 Marked
tion of deferasirox with antihistamine support and possible steroid osteoporosis and cortical thinning may predispose to pathologic
administration after which deferasirox may be reintroduced at a lower fractures of the extremities and compression fractures of the vertebrae
dose with gradual dose escalation. Reports of pancytopenia have (Fig. 40.10).
occurred in postmarketing reports, but mostly in patients with pre- Several abnormalities in the ribs may occur, including notching
existing hematologic disorders such as MDSs that are frequently and osteolytic lesions. 263,268 The ribs become very wide, especially at
associated with BM failure. the points of their attachment to the vertebral column. BM masses
A new oral tablet formulation of deferasirox (JadeNu) has recently may extrude from these sites, creating the appearance of paravertebral
269
been approved that does not require dispersion in liquid and can be masses and compressing the spinal cord. Although bone deformi-
taken once daily. Dosing is slightly different on a mg/kg dose, based ties and extramedullary hematopoiesis are uncommon in properly
on increased absorption of the new formulation, (e.g., patients on transfused patients with β-thalassemia major, it is frequently observed
20 mg/kg/d of the older Exjade formulation would take 14 mg/kg/d in patients with thalassemia intermedia whose BM is not suppressed
of JadeNu). Accordingly, this new formulation may have fewer by regular transfusions (see the section Thalassemia Intermedia).