Treatment options for chronic immune (idiopathic) thrombocytopenia purpura in children

Treatment Options for Chronic Immune (idiopathic) Thrombocytopenia Purpura in Children Michael D. Turantino immune (idiopathic) thrombocytopenic purpura (ITP) in children is usually acute and self-limiting, but may become chronic in 10% to 30% of patients. Salient issues in the treatment of childhood chronic ITP (clTP) include the following: the choice of immunomodulatory agent; the child’s desire for unrestricted physical activity; interventions to avoid or defer splenectomy; and, finally, choosing when (and how) to perform splenectomy. Treatment for children with clTP during childhood usually is extrapolated from that for acute ITP. Treatment with pooled intravenous immunoglobulin (IVlg) and anti-D immunoglobulin often gives an acute response followed by a predictable decay of platelet count. Cortlcosteroids usually lead to a platelet increase; however, the associated adverse effects of chronic usage are generally unsatisfactory for most children and adolescents. With pulsed, high-dose corticosteroids, a durable platelet response is the exception, not the rule. More aggressive immunosuppression is usually reserved for patients who are symptomatic and refractory to the above treatments, including splenectomy. Although the estimated success rate ranges from 70% to 90%, the long-term outcome of splenectomy in children with clTP in not well described. In addition, the risk of fatal postsplenectomy infections is significant. A familiar initial strategy among pediatric hematologists thus involves deferral of splenectomy with the reasonable possibility of spontaneous recovery. Corticosteroids, anti-D, and IVlg are effective, temparizing medical alternatives to splenectomy in treating clTP in children. Quality-of-life measurements in children with clTP may help to stimulate the development of new approaches. Semin Hematol37(suppll):354l. Copyfight 0 2000 by W.B. Saunders Company.

I

MMUNE (IDIOPATHIC) thrombocytopenit purpura (ITP) in children is largely an acute, self-limited illness. Approximately 20% of children diagnosed with ITP will continue to have thrombocytopenia beyond 6 months, defining the chronic condition.l-9 The debate over whether to intervene with immune modulation and, if so, with which agent, perhaps overshadows the issuestroubling the atypical pediatric patient whose thrombocytopenia persists long enough to be considered chronic. Splenectomysparing options for children with chronic ITP (cITP) are usually extrapolated from the those used for the acute form of the disease.Whether that is the optimal management is unknown, but it reflects the current state of limited options concerning treatment of pediatric cITP. For some children and adolescents with cITP, this results in a significant limitation of daily activity. The 3 most familiar splenectomy-sparing strategies for pediatric cITP remain corticosreroids, anti-D, and intravenous immunoglobulin (IVIg). The former is classically prescribed at the lowest effective daily or alternate-day dose after an initial period of daily dosing in the range of 1 to 4 mg/kg. Since the adverse effects Seminars

in Hematology,

Vol37,

of corticosteroids are intolerable for many children and adolescents, noncompliance with this regimen becomes a major issue. Daily corticosteroid use, therefore, is not a popular treatment for cITP in this group of patients. Furthermore, adverse long-term effects of this approach are not well defined.

High-Dose

Dexamethasone

In 1994, Anderson reported on the use of high-dose dexamethasone in 10 adult patients with cITP. Six of IO had been splenectomized and most had received multiple therapies. A sustained responserate of 100% was reported.lO These promising results have not been reproduced in children with cITP (Table 1). The 4 studies cited in Table ll’-l* were published in the wake of Anderson’s study and, therefore, fail From

University

of Louisville

School of Medicine,

Louisville,

KY. Address reprint requests to Michael I). Tarantino, MD, University of Louisville School of Medicine, J71 S Floyd St, Suite 300, Louisville, KY 40202. Copyright 0 2000 by W.B. Saunders Company 003 7-l 963/00/3 701-I 004$10.00/0

No 1, Supp/ I (January),

2000:

pp 35-41

35

36

Michael D. Tarantino

Table

Kuhne

Chen

Pulsed

Authors

et aI11

11

22 mg/m’/d dX6mo

17

20 mg/m*/d X 4 dX6mo 20-25 mg/m2/d x 4 d X 2-7 mo 40 mg/kg/d (max, 40 mg/d) X4dX6mo

Borgna-Pignatti Adams

1. High-Dose,

n

et alI3 et alI4

Abbreviations: concentration

et ali2

7 7

Dexamethasone

Dose

SCR

X 4

for clTP in Children SPR

TR

NR

l/11

3/ll

7/U

7/11

5/17

O/l7

7117

5/17

7

l/7

6/7

O/7

O/7

l/7

2/7

4/7

Major

Fatigue, lO/ll Moodiness, 9/11 Flushing, 7/11 Headache, 5/11 Irritability, 5/11 Fatigue, 9/17 Irritability, 6/17 Fatigue, 2/7 Epigastric pain, l/7 Pain, 6/7 Acne, 4/7 Weight gain, 3/7 Fatigue, 2/7

SCR, sustained complete response (26 months following completion of corticosteroid regimen) >15O,OOO/~L; SPR, sustained partial response; TR, temporary response; NR, no response.

to report on truly long-term effects (good and bad) of the high-dose dexamethasone regimen. At our institution, 2 of 10 children followed for greater than 3 years after receiving the dexamethasone regimen described by Andersonlo have had a durable complete response with platelet counts consistently greater than lSO,OOO/pL. Another 6 children have been observed for 2 to 36 months. The profile of adverse effects was not unlike those cited in Table 1 (unpublished data). Review of the published caseseriessuggests that a minority of pediatric patients do have a durable response to the short-pulse, high-dose dexamethasone treatment. Further investigations are needed, however, to determine the role of dexamethasone in cITP of childhood.

IVIg Immunoglobulins are typically prescribed episodically, based on a threshold platelet count or hemorrhage. The inherent limitation of episodic immunomodulation therapy for this population is its uncertain time of treatment. More frequent platelet counts and treatments may occasionally be required, especially for the physically active patient. Such episodic immunoglobulins will allow safe platelet levels to be reached and maintained, which would temporarily allow for more normal physical activity. In contrast to high-dose, pulsed dexamethasone, periodic treatment with IVIg yields ad-

SE,

with platelet

vantages, including a high rate of response and favorable (depending on the definition used) duration of response. This was first reported by Imbach et al in 198115 for acute ITP and later by Bussel et all6 as a legitimate means to defer splenectomy in childhood cITP. Several reports document the success in temporary platelet count elevation with pooled immunoglobulin in cITP.16-19 The cost-effectiveness of periodic IVIg infusions over splenectomy for younger children with cITP was described by Hollenberg et al,*O at a time when IVIg preparations were not marketed as competitively as today. In the current era of managed health care, an updated cost-effectiveness analysis, to include the use of laparoscopic splenectomy, may influence therapeutic decisions. The duration of response, defined as the time between IVIg treatments, usually gives a hyperbolic decay of platelet count, leaving the patient thrombocytopenic for much of the time between treatments. In addition, the acute adverse effects of IVIg treatment are not negligible. *l The more common side effects of fever, flushing, and headache may be debilitating for 1 to 3 days after infusion. Rarely, aseptic meningitis may occur. ** A concern overshadowing the acute toxicities of pooled immunoglobulin products is the risk of transmission of infectious agents. Transmission of infectious particles may occur, as seen in the recent cases of hepatitis C infection,*3 or remain theoretical, ie, the transmissible spongiform encephalopa-

Tqea.tment of Chronic ITP in Children

thies (TSE). For the former, viral reduction steps added to the immunoglobulin processing have substantially reduced the risk of infection transmission. For the latter, a deeper understanding of the actual infectious agent, presumed currently to be a prion, is needed to better assesswhether blood products can transmit these agents. The on-going International Early Chronic ITP Trial directed by Drs Kuhne and Imbach of the University Childrens’ Hospital in Basel, Switzerland, is a much needed prospective investigation of treatment options for early cITP. This is a study of treatment outcomes in early (no more than 1 year from initial diagnosis) cITP. The goal of this study is to identify the strategy most effective at maintaining the platelet count at greater than 2O,OOO/pL. Because patients are randomized, the effect of spontaneous recovery during the second 6 months of disease will be controlled. Patients are randomized to receive standard-dose IVIg (0.8 g/kg) as a single intravenous infusion over several hours, high-dose dexamethasone (24 mglm’id) for 4 consecutive days repeated every 28 days for 6 cycles, or the therapy of the physician’s choice to include observation alone, anti-D immunoglobulin, or conventionally dosed corticosteroids. The concerted international effort is a commendable approach to addressing therapeutic dilemmas in this disorder.

Anti-D

Iimmunoglobulin

Anti-D is a plasma-derived, hyperimmune immunoglobulin with high-titer Rho(D) antibody. Early reports of anti-D use in cITP showed that most patients experienced a significant rise in platelet concentration.24-27 Since that time at least 3 studies have reported a high rate of response.28-30The broad experience of anti-D use in cITP suggests that this agent may be used successfully to defer splenectomy in childhood cITP, as reported by Andrew et al in 22 of 25 patients.29 Patients must be phenotypically Rho(D)+ to benefit from anti-D. Thus, approximately 15% to 20% of patients will be ineligible to receive anti-D. Anti-D has been shown to produce

37

favorable results with fewer side effects than IVIg in children with cITP.~~JI In the author’s experience with anti-D treatment, fever and headache are not uncommon, but are shortlived adverse effects and can be prevented or ameliorated in most caseswith diphenhydramine and acetaminophen premeditations. The shorter, 5- to 30-minute infusion time and lower cost relative to IVIg treatment make anti-D an attractive alternative for the treatment of ~1Tp.3~ The relatively small plasma donor pool used in the isolation of anti-D theoretically lessens the likelihood of infectious disease transmission. Until the unresolved issues surrounding TSE and other agents are reconciled, any therapeutic blood derivative will pose at least a theoretical risk of infection transmission.

Danazol Danazol is a synthetic steroid derived from ethisterone approved for use in the treatment of endometriosis and fibrocystic breast disease. Temporary platelet count elevation has been reported in the majority of adults with cITP receiving 50 to 800 mg of danazol daily for 2 months.33p3* Some adults with cITP experienced years of unmaintained remission after long-term therapy (>2 years).35 The pediatric experience with danazol for cITP is not as well described. However, Weinblatt et al described a favorable responsein 5 of 10 children.36 Potential deleterious effects on growth along with known adverse effects of virilization, lethargy, and weight gain may deter the use of danazol in pediatric cITP.

Other Therapies Agents such as cyclophosphamide,37 vinblastine38 vincristine,‘” azathioprine,*O dapsone,*l colchicine,42s43ct!-interferon,** ascorbate,*5 and combination chemotherapy46 have been reported to increase the platelet count in a minority of patients with cITP. With the exception of azathioprine, long-term remissions in patients with cITP are highly unusual. Considerable adverse effects, including leukemogenic potential (cyclophosphamide), the lack

38

Michael D. Tarantino

of extensive use in children, and the unlikely prospect for a durable effect, have limited the use of these agents to splenectomy failures.

Splenectomy If any aspect of splenectomy for children with cITP is widely accepted in the medical literature, it is that splenectomy produces a much higher rate of complete remission or response than any other therapy.1-6~s~47~48 Approximately three fourths of children will have a sustained, complete platelet response following splenectomy. Only one trial, however, specified a follow-up period of at least 4 years and reported a substantially lower response rate compared with that after 1 year.* This raisesthe question as to whether there may be a not insignificant 5-, lo-, and 20-year relapse rate following splenectomy. Splenectomy is the invasive surgical removal of an important reticuloendothelial organ, especially in younger children. Any seemingly impressive response rates should be interpreted with caution. The rate of fatal postsplenectomy sepsis in reported studies rivals or exceeds the rate of fatal intracranial hemorrhage from ITP.*a-53 The American Society of Hematology practice guidelines for treatment of ITP suggests that splenectomy in pediatric patients be reserved for those with persistence of severe (
open approach. This may be a function of the procedural limitations and the surgeon’s technical skill and experience. No individual feature of cITP is asserted to consistently predict a patient’s response to splenectomy. Several parameters have been suggested, but remain at best unconfirmed. It has been suggested that a patient’s platelet response to corticosteroids56 or IVIg5’ may correlate with subsequent success of splenectomy. Najean et a152suggest that the successof splenectomy is closely related to the pattern of indium11 l-labeled platelet destruction. Success of splenectomy was best when platelet destruction was primarily splenic and worst when primarily hepatic. For children with cITP persisting longer than 3 years, late spontaneous remission of cITP occurs, but at a very low rate. In 1993, Tait et a1s8 reviewed their own experience in Great Britain, as well as previous studies in the literature, and found that spontaneous remissions have been reported up to 10 years after diagnosis of ITP. A large study by Walker and Walker* found that 6% of patients experienced a spontaneous remission 3 to 6 years after diagnosis. The additive weight of splenectomy failure, acute and late morbidity of splenectomy, the low rate of mortality of cITP itself, and the chance of late spontaneous remission of thrombocytopenia may lead some patients and physicians to defer splenectomy indefinitely in childhood cITP.

Summary Treatment regimens for cITP are generally based on platelet count thresholds since spontaneous hemorrhage is unlikely at a level of Z30,000/pL. Recommendations regarding the restrictions of physical activity in children with cITP raise medical and medicolegal considerations. The day-to-day uncertainty of the platelet count makes global recommendations difficult. In addition, previous studies of ITP have not addressedthe risk of hemorrhage during the various sports activities. Therefore, the prescription for restriction of physical activity is at the discretion of the physician. The author recommends restriction from contact sports (ie,

Tmztment

of Chronic

football, soccer) until the platelet count is consistently above lOO,OOO/~L. Most noncontact sports can be safely enjoyed with a platelet count greater than 3O,OOO/pL. Serious athletes may desire more frequent platelet count measurements and treatment during their participation. If one considers splenectomy a procedure to avoid or defer, then “splenectomy-sparing” strategies must be effective, noninvasive, easily administered, reasonably economical, and acceptable to the patient. Preliminary results with high-dose dexamethasone therapy have been somewhat disappointing. Anti-D or IVIg can temporarily raise the platelet count in about 90% of children with cITP, but regular monitoring and periodic re-treatment are required. Since anti-D is much easier to administer and less costly than IVIg, potential strategies might include alternative dosing routes and schedulesi2J9 to minimize the risk of severe thrombocytopenia.

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et al: home pur-