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Pulsed-Dosing With Oral Sodium Phenylbutyrate IncreasesHemoglobin F in a Patient With Sickle Cell Anemia
Patrick Hines, MD, PhD,1,2,3 George J. Dover, MD,1,2,3,4 and Linda M.S. Resar, MD1,2,3,4*
INTRODUCTION
Effective and safe agents that increase hemoglobin F (HbF) are
needed because elevations in HbF correlate with improved outcomes
for patients with hemoglobin SS (HbSS) [1–3]. While hydroxyurea
effectively increases HbF, decreases sickle cell disease-related
complications, and improves survival in patients with HbSS [4–9],
the concern for side effects and potential risk for malignancy may be
limiting its widespread use. Butyrates are naturally occurring fatty
acids originally used to treat children with urea cycle disorders [10]
and later found to increaseHbF production [11–18]. Over 100 person
years of butyrate therapy in other disorders has demonstrated no
serious side effects [10].Wepreviously showed that daily oral sodium
phenylbutyrate (OSPB) induces HbF production in patients with
HbSS [14,17]. The high doses and daily administration, however,
have limited its use. More recently, pulsed-dosing with intravenous
arginine butyrate resulted in sustained elevations in HbF in HbSS
patients [16,18], although the mode of delivery is not practical for
most patients. Here, we report a patient treated with pulsed-dosing of
OSPB who had sustained increases in HbF.
CASE REPORT
A9-year-oldAfrican–AmericanmalewithHbSS followed at the
Johns Hopkins Hospital was enrolled in a study to determine if
pulsed-dosing with OSPB could induce HbF synthesis. We assessed
F-reticulocytes as the primary outcome because they are an early
indicator of HbF synthesis [17]. HbF levels were assessed as a
secondary endpoint. Patients were eligible for this trial if they had
responded to daily OSPB in our previous trial [17]. One pulse of
OSPBwas defined as 4 consecutive days given as a single dose each
day. The interval between doses was measured from Day 1 of each
pulse to Day 1 of the subsequent pulse. The initial interval between
pulses was 4 weeks because intravenous therapy had been effective
when given at 4-week intervals. If F-reticulocytes were not at least
twice their baselinevalue after 4weeks in two subsequent pulses, the
interval was decreased by 1 week to 3 weeks for two subsequent
pulses. If F-reticulocytes did not double after 3 weeks in two pulses,
the interval was decreased to 2 weeks. Similarly, if F-reticulocytes
did not double after 2 weeks for two pulses, the interval was
decreased to 1 week such that the patient received 4 days on OSPB
therapy and 3 days off therapy. If this was not effective in
maintaining F-reticulocytes to at least double their baseline values
after 4 weeks, the trial was considered a failure and discontinued.
F-reticulocytes [13], HbF, complete blood counts, and reticulo-
cyte counts were measured on days 1 and 4 of each pulse for weeks
1–27,weekly forweeks 28–38, thenmonthly to every othermonth to
limit phlebotomy. Themedication was administered in our outpatient
Pediatric Clinical Research Unit for the first 13 pulses. Compliance
was estimated with pill counts. The study was approved by the Food
andDrugAdministration and the Institutional ReviewBoard at Johns
Hopkins University. Informed consent and assent were obtained from
the patient’s parent and patient, respectively, according to the
Declaration of Helsinki.
From the original four of six patients who responded to daily
OSPB, one enrolled in this trial to receive pulsed therapy. Of the
remaining three patients, one developed a stroke 4 months after
receiving daily OSPB and was, therefore, not eligible for this trial.
Another patient developed frequent painful crises managed with
transfusion therapy. The third patient was no longer willing to take
the pills. As we previously reported, this patient (#2) [17] was first
treated with daily OSPB at an initial dose of 1.0 g/day. The dosewas
increased by 1.0 g/day at weekly intervals to 5.0 g/day (5.7 g/m2)
at which point the F-reticulocytes increased to at least twice
their baseline values (from 9.3%� 2.3% to a peak level of
24.7%� 1.2%). HbF also increased from 4.7% to a peak of 11.9%
after a total of 22 weeks of therapy [17].
After stopping daily OSPB therapy, the patient remained off
therapy for 4weeks until the F-reticulocytes returned to baseline levels
(8.7%� 1.2%). HbF fell from a peak of 11.9% to 9.2%. He then
started pulsed OSPB at 5 g/day (Table I, Fig. 1) and F-reticulocytes
remained near baseline after the first 4-week interval (8.0%þ/�2.0%)
——————1Hematology Division, The Johns Hopkins University School of
Medicine, Baltimore, Maryland; 2Department of Pediatrics, The Johns
Hopkins University School of Medicine, Baltimore, Maryland;3Department of Oncology, The Johns Hopkins University School of
Medicine, Baltimore, Maryland; 4Department of Medicine, The Johns
Hopkins University School of Medicine, Baltimore, Maryland
Patrick Hines’s present address is Children’s Hospital of Philadelphia,
Philadelphia, Pennsylvania.
*Correspondence to: L. M. S. Resar, Division of Pediatric Hematology,
John Hopkins Medical Institute, 720 Rutland Avenue, Ross 1125,
Baltimore, MD 2105. E-mail: lresar@jhmi.edu
Received 4 May 2006; Accepted 18 September 2006
Increasing hemoglobin F (HbF) appears to be beneficial forpatients with sickle cell anemia. We previously demonstrated thatdaily, oral sodium phenylbutyrate (OSPB) induces HbF synthesis inpediatric and adult patients with hemoglobin SS (HbSS). The highdoses and need for daily therapy, however, have limited its use.Here, we report a patient treated with pulsed-dosing of OSPB for
over 3 years. This patient developed a modest, but sustainedelevation in HbF over the course of therapy without side effects.Although larger studies are needed, this case demonstrates thatpulsed-dosing with OSPB enhances HbF synthesis. Pediatr BloodCancer 2008;50:357–359. � 2007 Wiley-Liss, Inc.
Key words: hemoglobin F; pulsed-dosing; sickle cell anemia; sodium phenylbutyrate
� 2007 Wiley-Liss, Inc.DOI 10.1002/pbc.21104
Brief Reports 357
and increased slightly after the second 4-week interval (12.0%þ/
�2.0%). HbF continued to decline to 7.0% after the first 4-week pulse
and 6.7%after the second 4-week pulse. The intervalwas decreased to
3weeks and F-reticulocyte remained in a similar range (10.7� 1.2%).
The F-reticulocytes also remained in a similar range following 2-week
intervals (12.7%�2.0%). When the patient was placed on 1-week
intervals, the F-reticulocytes increased to greater than double the
baseline level to 21.3%� 1.2% after 4 days on therapy and 3 days off
therapy. The patient continued the pulses for a total of 177 weeks
(Table I, Fig. 1).
The highest percent F-reticulocytes (30.7� 1.2%) was obtained
on Day 4 of the first pulse. Once the patient was placed on weekly
pulses, the F-reticulocytes remained on average between 2 and
3 times their baselinevalue (range 8.0%–30.7%),which is similar to
the F-reticulocytes on daily therapy (range 8.0%–24.7%). The HbF
reached its nadir of 5.9% on week 15. Once the interval between
pulses was decreased to 1 week (on week 18 of this trial), the HbF
began to rise to a maximal level of 8.6% after 103 weeks. (The
starting HbF value of 9.2% reflects an increase above the baseline
value of 4.6% after taking daily, OSPB for 22 weeks). After
26weeks, he began taking theOSPB in two divided doses because of
difficulty taking the pills as one dose. After 3 years, the patient no
longer wanted to take the pills and discontinued therapy. F-
reticulocytes were 22.0� 2.0% and HbF was 8.4% at the
completion of this trial. Compliancewas estimated at 99%.Notably,
the patient had no side effects. Other hematologic parameters
(hemoglobin, hematocrit, reticulocyte count) did not change.
Before startingOSPB, this patient had an average of two hospital
admissions/year from birth until age 8 years (range 1–4). Reasons
for admission included fever (5), fever and dactylitis or pain (3), pain
(1), fever, pulmonary infiltrate, þ/�reactive airway disease (RAD)
(6), fever and RAD (1), and hallucinations of unclear etiology (1).
He was hospitalized for fever, RAD, and a pulmonary infiltrate 1
week after starting therapy with daily OSPB, but had no hospital-
izations over the subsequent 3 years on pulsed, OSPB. His mother
also felt that he was subjectively better on OSPB. Of note, he also
had no hospitalizations over the past 4 years since stopping OSPB,
except for one admission for repair of an inguinal hernia.
DISCUSSION
Here, we describe a patient treated with pulsed, OSPB who
developed a modest, but sustained elevation in HbF to a level almost
twice his baseline (8.6%vs. 4.7%). Similar increases in themeanHbF
(5.1% vs. 8.6%) were reported in the large Multicenter Study of
Hydroxyurea trial that first demonstrated a significant decrease in the
incidence of painful crisis and acute chest syndrome inHbSS patients
on hydroxyurea [5].Although hydroxyurea is effective in raisingHbF
[5–9], concerns about the potential risks of long-term use may have
limited its widespread use. Butyrates are a class of compounds with a
low side effect profile and no apparent risks for malignancy based
on decades of experience with patients with metabolic disorders
[10–18].Adrawback to their use, however, hasbeen the large number
of pills required [14,17]. More recently, intravenous, pulsed arginine
butyrate was shown to be effective in increasing HbF, although the
mode of delivery makes this therapy inaccessible to most patients
[16,18]. These investigators also provide evidence that intravenous
butyrates enhance the translational efficiency of gamma globin as a
mechanismfor increasingHbF [18]. Thus, amajor challenge hasbeen
to develop an optimal and practical dosing regimen for butyrate in
HbSS patients.
Given the success of pulsed, intravenous arginine butyrate, we
designed a trial to assess pulsed OSPB. Our patient had an initial,
gradual decline in HbF levels until the interval between pulses was
reduced to 1 week. F-reticulocytes doubled and HbF increased to a
peak of 8.6% by 103 weeks when therapy was given for 4 days each
week. Interestingly, this patient had a higher peak F-reticulocyte
count on pulsed therapy (30.7%) compared to daily therapy
(24.7%), although the peak HbF (8.6%) was lower than the peak
achieved on daily therapy (11.9%). The discordance between F-
reticulocytes and HbF on pulsed OSPB suggests that factors other
than F-reticulocyte levels contribute to increases in HbF, at least for
this patient. Alternatively, F-reticulocytes may have dropped to
lower levels on pulsed OSPB between visits. We conclude that both
daily and pulsed OSPB induce HbF production, although daily
therapy was more effective for this patient. Further studies with oral
butyrate compounds are warranted to identify more effective
compounds and dosing regimens, either alone or in combination
with other therapy.
Pediatr Blood Cancer DOI 10.1002/pbc
TABLE I. Comparison of F-Reticulocytes and Hemoglobin F After Therapy With Daily or Pulsed Oral SPB
Total weeks treated
F-reticulocytes (%) HbF (%)
Pre �SD Peak �SD Week Pre/nadir Peak Week
Daily 22 9.3 2.4 24.7 1.2 22 4.7/4.7 11.9 22
Pulse 177 8.7 1.2 30.7 1.2 1 9.2/5.2 8.6 103
Fig. 1. F-reticulocytes and HbF on daily versus pulsed, oral SPB by
week. Changes in F-reticulocyte and HbF values over time on oral SPB
therapy are shown. This patient was first treated with daily, oral SPB
therapy for 22 weeks (beginning on day 0), followed by a 4-week
washout period where no SPB was given. The vertical line indicates the
time pulse therapy was started.
358 Brief Reports
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Low Daytime Pulse Oximetry Reading Is Associated WithNocturnal Desaturation and Obstructive Sleep Apnea
in Children With Sickle Cell Anemia
John F. Spivey, MD, Elizabeth C. Uong, MD, Robert Strunk, MD, Sarah E. Boslaugh, PhD, MPH,and Michael R. DeBaun, MD, MPH*
INTRODUCTION
Increased attention has recently been focused upon the
prevalence of sleep-disordered breathing, specifically nocturnal
desaturation and obstructive sleep apnea (OSA) in children with
sickle cell anemia (SCA) [1–5]. Recent studies have demonstrated
that a decreased mean nocturnal oxygen saturation (SpO2) is
associated with an increased rate of both painful episodes and
cerebrovascular accidents in children with sickle cell disease [6,7].
In healthy children, a normal physiological decrease in nighttime
versus daytime SpO2 is expected [8–10]. Daytime SpO2 assess-
ments are becoming a routine practice in many sickle cell disease
A retrospective medical record review was established to test thehypothesis that in children with sickle cell anemia (SCA), a daytimeoxygen saturation (SpO2) �94% is associated with nocturnaldesaturation with or without obstructive sleep apnea (OSA). Twentychildren had a resting SpO2�94% and an abnormal polysomnogram(PSG). Seven patients had OSA and thirteen patients had nocturnal
desaturation. The average daytime SpO2 correlated with theaverage nighttime SpO2 (Spearman correlation coefficient¼0.453;P¼ 0.045). Our results indicate that in children with SCA, adaytime SpO2 �94% is a reasonable threshold to recommend apulmonary evaluation, including a PSG. Pediatr Blood Cancer2008;50:359–362. � 2006 Wiley-Liss, Inc.
Key words: nocturnal desaturation; obstructive sleep apnea; polysomnogram; sickle cell anemia
——————Department of Pediatrics, Washington University School of Medicine/
St. Louis Children’s Hospital, St. Louis, Missouri
Grant sponsor: Training grant; Grant numbers: T32 HL07873, R01
HL079937-01.
*Correspondence to: Michael R. DeBaun, Washington University
School of Medicine, 4444 Forest Park, Campus Box 8519, St. Louis,
MO 63108. E-mail: DeBaun_M@kids.wustl.edu
Received 28 March 2006; Accepted 7 August 2006
� 2006 Wiley-Liss, Inc.DOI 10.1002/pbc.21054
Brief Reports 359
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