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