Page 660 - Hematology_ Basic Principles and Practice ( PDFDrive )

562 Part V Red Blood Cells

transfusions and chelation monitoring. Future efforts should be initi- to 32% depending on the prophylaxis regimen, and the incidence of
ated to improve the care of adult patients with thalassemia, including chronic GVHD is 27% in patients receiving BM hematopoietic stem
understanding the pathology of the disease and training new genera- cells from a parental or sibling human leukocyte antigen (HLA)-
350
tions of hematologists with an understanding of thalassemia identical donor. In addition, recent studies suggest HLA-identical
syndromes. or 1-antigen-mismatched related nonsibling donors can be performed
Screening tests are also an important component of ongoing care with high thalassemia-free survival rates. 351
in thalassemia. Currently, the most common cause of mortality in In view of the available evidence, stem cell transplantation from
adults with thalassemia is related to cardiac disease and arrhythmias. a partially HLA-matched relative is not routinely advisable, although
These patients also have other chronic illnesses including cardiomy- it may be considered in extreme situations when transfusion support
opathy, hepatic disease, endocrinopathies, osteoporosis, hypogonad- is impossible or life threatening when a patient is completely non-
ism, pulmonary hypertension, and ongoing infectious risk from compliant with any type of iron chelation therapy.
splenectomies. Recommended screening tests are shown in Tables
40.1–40.2, based on recommendations from the Thalassemia Inter-
national Federation (www.thalassemia.org.cy). Regular follow up Experimental Therapies
with an internal medicine primary care physician is also recom-
mended to make sure adults are aware of current screening and Enhancement of β and γ Gene Expression
treatment guidelines applicable to the general population, for example
age-appropriate cancer screening, an area where adult patients may Active γ-globin genes are hypomethylated in utero but are methylated
not have previously been referred because of historically shorter and inactive after birth. Hypomethylation of the γ-globin genes can
lifespans. be induced by the drug 5-azacytidine; indeed, short-term administra-
tion of this drug produced the predicted effect in vivo. 352–354 Despite
much subsequent experimental work, it remains unclear whether the
Hematopoietic Stem Cell Transplantation effect was attributable to direct stimulation of fetal genes by demeth-
ylation or to recruitment and accelerated differentiation of primitive
There is now extensive experience with transplantation, with well burst-forming unit–erythroid progenitor cells, which have greater
346
over 3000 patients having undergone transplantation. Risk classi- potential to produce Hb F. 355–357 Hydroxyurea has an effect on burst-
fication is based on hepatomegaly, the degree of portal fibrosis, and forming unit–erythroid similar to that of 5-azacytidine and is a safer
347
the regularity of prior iron chelation therapy. In class 1 without drug for long-term use. 356,358 Short-term as well as longer trials with
adverse factors, the overall survival rate is 95%, and the event-free hydroxyurea have been reported in a number of patients with
survival rate (without thalassemia) is 90%; class 2 patients with one thalassemia. 359–366 Hb F levels frequently increase without a propor-
or two risk factors have an 85% survival and an 81% event-free tionate increase in total Hb level. A small improvement in total Hb
survival; and class 3 patients with all three risk factors have only 64% level occurs in some patients with thalassemia intermedia but usually
and 62% overall and event-free survival rates, respectively (Fig. does not exceed 1–2 g/dL. 363,364 Some patients report improvement
347
40.12). Advances in conditioning regimens have considerably in their overall sense of well-being even in the absence of an improve-
363
improved the outcome of class 3 patients who are younger than 17 ment in the anemia. This may be a result of suppression of
years of age. Preparatory chemotherapeutic regimens to enhance abnormal erythropoiesis, an effect that may also explain the value of
immunosuppression and eradicate thalassemic clones using hydroxy- hydroxyurea in the treatment of extramedullary hematopoietic
367
urea, azathioprine, fludarabine, busulfan, and cyclophosphamide masses. Although one patient with thalassemia major had sufficient
have increased the survival rate of class 3 patients to 93%; the rejec- improvement in his Hb level to end his dependency on regular
365
348
tion rate fell to 8%. These favorable results have not been repro- transfusions, most transfusion-dependent patients have shown no
duced in the older, more heavily iron-overloaded patients who remain clinical benefit. Recombinant EPO has produced inconsistent
349
high risk for transplant-related mortality. Stem cell transplantation responses in patients with thalassemia intermedia. 368–372 When the
can fail or be lethal owing to its immunologic complications. The series are combined, approximately 40% of patients have an increase
overall incidence of acute graft-versus-host disease (GVHD) is 17% in Hb level of 2–3 g/dL. EPO has shown little benefit overall in
patients with thalassemia major, although there are occasional reports
of patients whose transfusion requirements were reduced or elimi-
nated. 371,373 Decitabine has been used to induce sustained increase of
Hb F and total Hb in patients with sickle cell disease with the low
1.0 95% likelihood of neutropenia and may have a similar effect in thalassemia
90% but its therapeutic efficacy remains to be proven. 374,375 Although the
0.8 pharmacologic enhancement of Hb F production remains an attrac-
tive strategy in the management of thalassemia, the results to date
strongly suggest the need for new agents or new combinations of
Probability 0.4 Event-free survival agents.
Survival
0.6
Another potential strategy is to develop techniques to silence Hb F
Rejection
376
in the reactivation of Hb F expression. Other important molecular
0.2 Nonrejection mortality suppression. Recently, the knock down of BCL11A expression resulted
5% targets to induce Hb F include KLF1, MYB, SOX6, MiRNAs, and
5% histone acetylase, which may lead to other targeted approaches to
0.0 enhance Hb F. 377–385 BCL11A is a zinc-finger transcriptional repressor
0 2 4 6 8 10 12 active in erythroid cells and in other hematopoietic lineages. Several
386
Year studies indicate that BCL11A silences γ-globin. 386–388 BCL11A does
Fig. 40.12 KAPLAN-MEIER PROBABILITIES of survival, event-free not bind the γ-globin promoter but the LCR and different intergenic
survival, rejection, and nonrejection mortality for 121 class 1 thalassemic regions in the globin locus that were previously tied with γ-globin
patients younger than 17 years receiving bone marrow transplants from repression. 386,389–392 KLF1 (also known as EKLF) is an erythroid
human leukocyte antigen–identical donors after preparation with busulfan transcription factor activating BCL11A and playing a major role
(14 mg/kg), cyclophosphamide (200 mg/kg), and cyclosporine alone, from in the switch from fetal to adult Hb. 393–396 Thalassemia intermedia
January 2, 1986, through April 10, 1997, and calculated on May 15, 1997. patients with mutations in the CACCC box of the β-globin promoter
(Adapted from Lucarelli G, Galimberti M, Giardini C, et al: Bone marrow trans- (which is recognized by KLF1) demonstrate significant elevation of
plantation in thalassemia. Ann N Y Acad Sci 850:270, 1998.) Hb F. 397,398 Recent studies in Chinese populations with thalassemia