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Blood, Vol. 93 No. 6 (March 15), 1999:
pp. 1787-1789
INTRODUCTION: FOCUS ON HEMATOLOGY
Induction of Fetal Hemoglobin in Sickle Cell Disease
By
H. Franklin Bunn
From the Division of Hematology, Brigham and Women's Hospital,
Boston, MA.
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ARTICLE |
THIS ISSUE OF BLOOD features a report by Atweh
et al1 on the induction of fetal hemoglobin (Hb F) by pulse
butyrate. This study is a solid addition to the recent and gratifying
momentum in the development of effective therapy for sickle cell
disease. Underlying this report is a series of novel and convincing in vivo studies extending from model systems in the chicken,2 sheep,3 and baboons4-6 to observations on
babies of diabetic mothers7 and on patients with metabolic
disorders8 and hemoglobinopathies,9,10 all
indicating that butyrates and other short chain fatty acids can cause
significant increases in the levels of Hb F. Our current understanding
of the molecular pathophysiology of sickle cell disease11-13 strongly indicates that patients would derive
considerable benefit from pharmacological induction of Hb F.
The gold standard to which butyrate and related compounds must be
compared is hydroxyurea, an agent now accepted as safe and effective
therapy for sickle cell disease. Initial studies on both hydroxyurea
and butyrate focused on the efficacy with which they cause upregulation
of the  globin gene, thereby increasing the production of Hb F
( 22). In the earlier clinical trials, continuous administration of intravenous (IV) butyrate initially induced a significant increase in Hb F, but with further therapy, the
levels tended to fall back toward baseline. As Atweh et al1 now report, this tachyphylaxis can be obviated by intermittent or pulse
therapy. This treatment resulted in sustained and marked increases in
the percentage of Hb F (Table 1). The
investigators compare these impressive increases with the much more
modest induction observed in the national multicenter cooperative
hydroxyurea (MSH) trial.14,15 However, this is not an apt
comparison, because the two studies differ markedly on issues of
patient compliance and study design. The pulse butyrate protocol,
involving 4-day IV infusions, necessitated full patient cooperation. In
contrast, the design of the cooperative hydroxyurea study required that each participating medical center enroll a minimum number of patients. As a result, the motivation of some of these patients was suspect and,
indeed, compliance was problematic.15 Moreover, because of
the MSH protocol design, even among patients who were fully compliant,
many were undertreated and therefore did not achieve maximal levels of
Hb F. It is likely that both patient cooperation and adequacy of
treatment were considerably greater in earlier studies of much smaller
groups of SS patients treated with hydroxyurea.16-19 As
shown in Table 1, in these smaller studies the induction of Hb F was
much more impressive than what was observed in the MSH cooperative
study. The responses achieved in the 15 adults who participated in
these studies are comparable to the robust inductions of Hb F reported
in children treated with hydroxyurea20,21 (not shown) as
well as to the responses in adults treated with pulse butyrate.
Another consideration that is important in interpreting reports on
pharmacological induction of Hb F is the antisickling effect on
individual red blood cells. In both normal individuals as well as in
patients with sickle cell disease, Hb F is distributed in only a small
proportion of cells, the so-called F cells. The remaining cells are
virtually devoid of Hb F. Before drug treatment, the F cells of most SS
patients contain approximately 15% Hb F. This amount is more than
adequate to inhibit intracellular polymerization. As shown in Table 1,
pulse butyrate results in a marked (nearly 2-fold) increase in Hb F per
F cell. This increment is wasted on the already unsickleable F cell. In
contrast, the increase in F per F cell is more modest in patients
treated with hydroxyurea (Table 1). Thus, a given increment in Hb F
resulting from hydroxyurea therapy is distributed over a larger
proportion of the patient's red blood cells and would therefore be
more likely to be clinically effective.
Because hydroxyurea was developed and is widely used as an
antineoplastic agent, there has been understandable fear that it may be
teratogenic and/or tumorigenic. This concern is heightened by the
prospect of decades of drug exposure and thus has been a major impetus
in the search for other pharmacological inducers of Hb F. Although
experience in the use of hydroxyurea in potentially child-bearing
individuals is limited, there is no apparent increase in birth defects
among infants born to mothers or fathers who were taking the drug at
the time of conception. Likewise, the risk of hydroxyurea
triggering neoplastic transformation appears to be very small. As the
report of Atweh et al1 points out, sodium butyrate
suppresses cell growth and, like hydroxyurea, has been used as an
antineoplastic agent.22 Unlike many anticancer drugs,
neither agent causes direct chemical modification of DNA and,
therefore, would not be expected to be mutagenic.
In view of the inherent complexity of both sickle cell pathophysiology
and the pharmacology of hydroxyurea and butyrate, it is critical to
examine the mechanisms underlying the efficacy of each drug. In the
case of hydroxyurea, there is convincing evidence that the drug not
only induces a robust and sustained increase in F cells, but also has
antisickling effects as assessed by a marked reduction in the fraction
of irreversibly sickled cells and hyperdense cells along with an
increase in cation content and deformability.17-19 These
highly relevant measurements need to be made on patients before and
during treatment with butyrate. Even though hydroxyurea is a
myelosuppressive agent, treatment of SS patients results in a small but
significant increase in hemoglobin levels, a paradox that can only be
explained by the drug's causing a marked amelioration in hemolysis.
This conclusion has been documented by reductions in serum
nonconjugated bilirubin and LDH and by a prolongation of red blood cell
life span.17,18 The 11 patients treated with pulse butyrate
developed a 13% increment in hemoglobin levels, comparable to what has
been observed with hydroxyurea. It will be important to learn whether
pulse butyrate is as effective as hydroxyurea in lowering hemolytic rate.
A major surprise that emerged from clinical studies of SS patients
treated with hydroxyurea is that induction of Hb F is not the only, and
perhaps not the major, contributor to the drug's efficacy. The benefit
of hydroxyurea therapy may be due in part to its well-known ability to
suppress both erythropoiesis and myelopoiesis. Reticulocytes and young
(hypodense) (SS) red blood cells have particularly enhanced adherence
to vascular endothelium. A marked decrease in the adhesion of
patients' red blood cells to cultured endothelial cells is observed
within 2 weeks after initiation of hydroxyurea therapy, coincident with
a decrease in absolute reticulocyte levels and long before there is a
significant induction of Hb F.23,24 Suppression of
neutrophil production may be an even greater contributor to the
efficacy of hydroxyurea. A detailed multivariable analysis of data from
the MSH study showed that the percentage of F cells correlated
inversely with rate of pain crises only during the initial 3 months of
therapy. In contrast, there was a strong correlation between neutrophil
count and crisis rate throughout the 2-year study.15 Thus,
the modest neutropenia that accompanies hydroxyurea treatment may
contribute to the drug's efficacy. If myelosuppression is indeed a
blessing in disguise, this benefit would not be realized with pulse
butyrate therapy, a protocol that, by design, minimizes this effect.
Considerably more inquiry at the bench and at the bedside is needed to
determine whether butyrates and/or other short chain fatty acids can
either replace or supplement the use of hydroxyurea. The development of
safe and effective oral derivatives is essential for long-term
administration in a patient group with poor IV access. One hopes that,
as we enter the next millennium, academic medical centers, the
pharmaceutical industry, government funding agencies, and patient
volunteers all have the staying power to meet this challenge.
| |
FOOTNOTES |
Address reprint requests to H. Franklin Bunn, MD, Division of
Hematology, Brigham and Women's Hospital, 221 Longwood Ave, Room
LMRC-223, Boston, MA 02115.
| |
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