A dose of 75 μg/kg/d of i.v. anti-D increases the platelet count more rapidly and for a longer period of time than 50 μg/kg/d in adults with immune thrombocytopenic purpura

Authors

  • Gregg C. Newman,

    1. Divisions of Hematology/Oncology, 1Department of Medicine and 2Department of Pediatrics, New York Presbyterian Hospital – Weill Medical College of Cornell University, New York, NY, 3North Shore University Medical Center, Long Island, NY, and 4Cangene Corporation, Winnipeg, Manitoba, Canada
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  • 1 Maria V. Novoa,

    1. Divisions of Hematology/Oncology, 1Department of Medicine and 2Department of Pediatrics, New York Presbyterian Hospital – Weill Medical College of Cornell University, New York, NY, 3North Shore University Medical Center, Long Island, NY, and 4Cangene Corporation, Winnipeg, Manitoba, Canada
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  • 2 Erin M. Fodero,

    1. Divisions of Hematology/Oncology, 1Department of Medicine and 2Department of Pediatrics, New York Presbyterian Hospital – Weill Medical College of Cornell University, New York, NY, 3North Shore University Medical Center, Long Island, NY, and 4Cangene Corporation, Winnipeg, Manitoba, Canada
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  • 2 Martin L. Lesser,

    1. Divisions of Hematology/Oncology, 1Department of Medicine and 2Department of Pediatrics, New York Presbyterian Hospital – Weill Medical College of Cornell University, New York, NY, 3North Shore University Medical Center, Long Island, NY, and 4Cangene Corporation, Winnipeg, Manitoba, Canada
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  • 3 B. M. R. Woloski,

    1. Divisions of Hematology/Oncology, 1Department of Medicine and 2Department of Pediatrics, New York Presbyterian Hospital – Weill Medical College of Cornell University, New York, NY, 3North Shore University Medical Center, Long Island, NY, and 4Cangene Corporation, Winnipeg, Manitoba, Canada
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  • and 4 James B. Bussel 2

    1. Divisions of Hematology/Oncology, 1Department of Medicine and 2Department of Pediatrics, New York Presbyterian Hospital – Weill Medical College of Cornell University, New York, NY, 3North Shore University Medical Center, Long Island, NY, and 4Cangene Corporation, Winnipeg, Manitoba, Canada
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James B. Bussel, M.D., Associate Professor, Paediatric Hematology/Oncology, New York Presbyterian Hospital – Weill Medical College of Cornell University, 525 E. 68th Street, Payson 695, New York, NY 10021, USA. E-mail: jbussel@mail.med.cornell.edu

Abstract

Treatment with 75 μg/kg/d intravenous (i.v.) anti-D was compared with 50 μg/kg/d in a prospective randomized study of 27 RhD-positive, human immunodeficiency virus-negative, adult, acute, non-splenectomized patients with immune thrombocytopenic purpura (ITP) and platelet counts ≤ 30 × 109/l. The higher dose resulted in greater median d 1 (43 × 109/l vs. 7·5 × 109/l; P = 0·012) and d 7 (153 × 109/l vs. 64·5 × 109/l; P = 0·001) platelet increases despite no greater haemoglobin decrease. Children with acute ITP receiving 75 μg/kg/d had overnight platelet increases in seven out of nine cases. The duration of effect at the 75 μg/kg/d dose was 46 d vs. 21 d (P = 0·03). Adverse events were mild to moderate and ameliorated with prednisone and acetaminophen premedication.

Intravenous (i.v.) anti-D is a well-recognized treatment for RhD-positive, non-splenectomized children and adults with immune thrombocytopenic purpura (ITP) whose physicians desire to increase their platelet count (Salama et al, 1983; Bussel et al, 1991; Scaradavou et al, 1997). The toxicity profile is similar to that of i.v. Ig; however, the ‘standard dose’ of 50 μg/kg/d of i.v. anti-D requires 72 h to produce a clinically significant platelet increase (Bussel et al, 1991). Therefore, i.v. anti-D has not been recommended as first-line therapy to rapidly elevate the platelet count in severely thrombocytopenic patients (Bussel et al, 1991; Blanchette et al, 1994; Scaradavou et al, 1997).

This prospective, randomized study explored whether a higher dose of i.v. anti-D, 75 μg/kg/d, could more rapidly increase the platelet count than 50 μg/kg/d in 27 human immunodeficiency virus (HIV)-negative, adult, RhD-positive (Oksenhendler et al, 1988), non-splenectomized (Scaradavou et al, 1997) patients with platelet counts ≤ 30 × 109/l within 1 year of diagnosis with ITP (George et al, 1996). Nine consecutive children with acute ITP at diagnosis with platelet counts < 20 × 109/l also received this dose after the results in adults became manifest.

Prior to infusion of anti-D, 25 out of 27 patients received 650 mg of oral acetaminophen. Beginning approximately half-way through the study, patients also were given a single dose of prednisone, 20 mg, to reduce the side-effects of anti-D (see below). The study was approved by the Institutional Review Board.

Patients had a FBC (full blood count) on d 0, d 1 and d 7, and then weekly, following treatment. Platelet increases were compared for the two doses using the Wilcoxon signed-rank test. Time until the platelet count returned to ≤ 30 × 109/l defined the duration of effect. Changes in the haemoglobin concentration and adverse events were tabulated. Two-tailed probabilities by chance < 0·05 were considered significant.

The two treatment cohorts (75 and 50 μg/kg/d) were not different at entry for variables relating to their ITP, i.e. duration of ITP, starting platelet count and previous treatments such as prednisone.

The platelet counts following 75 μg/kg/d of i.v. anti-D therapy (Fig 1) showed a median overnight increase of 43 × 109/l (mean 35·2 × 109/l), whereas after 50 μg/kg/d it was only 7·5 × 109/l (mean 12·6 × 109/l) (P = 0·012). After 7 d, the median changes were 153 × 109/l (mean 192·8 × 109/l) and 64·5 × 109/l (mean 67·5 × 109/l) respectively (P = 0·001). At 24 h, 69·2% of patients receiving 75 μg/kg/d had a platelet count increase > 20 × 109/l, compared with only 21% receiving 50 μg/kg/d (P = 0·02). The single-dose prednisone premedication did not alter the platelet increase (or the haemoglobin decrease). The median overnight increase for the nine children was 41 × 109/l (mean 42·4 × 109/l); seven out of the nine had an increase > 20 × 109/l.

Figure 1.

The Y-axis is the platelet count × 109/l. The X-axis is time at d 0 and 1 d. Individual adult patient platelet counts before and 1 d after receiving 50 μg/kg/d (n = 14) (left) and 75 μg/kg/d (n = 13) (middle) of IV anti-D, respectively, are shown. The d 0 and d 1 platelet counts in nine consecutive paediatric patients treated with 75 μg/kg/d are shown on the right. All adult patients had initial platelet counts ≤ 30 × 109/l; those for children were < 20 × 109/l. The percentage of patients increasing by > 20 × 109/l 1 d after treatment was significantly greater in adult patients following a dose of 75 μg/kg/d than a dose of 50 μg/kg/d.

Following 75 μg/kg/d, the median duration of response was 46 d, whereas after 50 μg/kg/d, it was 21 d (P = 0·03). Nine out of 13 patients receiving 75 μg/kg/d had a duration of effect > 30 d compared with only 2 out of 14 patients receiving 50 μg/kg/d (P = 0·01).

No severe adverse events (AEs) were seen. Four out of 13 patients receiving 75 μg/kg/d had seven moderate intensity AEs (fever, chills, nausea) compared with 1 out of 14 patients receiving 50 μg/kg/d. For six of the seven moderate AEs following 75 μg/kg/d, no prednisone premedication had been given. Patients receiving 75 μg/kg/d had a total of 20 AEs in eight infusions without prednisone vs. seven AEs in five infusions with prednisone.

The decrease in haemoglobin was the same for both dosage groups (Fig 2). The three patients with the largest haemoglobin decreases, 3·0–3·5 g/dl on d 7, all received 50 μg/kg/d. No intravascular haemolysis was identified. Twelve out of 27 adults reported transient fatigue after anti-D infusion; this complaint was not related to the haemoglobin decrease. No significant changes were identified in vital signs, blood urea nitrogen (BUN) or creatinine levels. No evidence of coagulopathy was seen.

Figure 2.

The Y-axis represents the decrease in haemoglobin level from baseline in g/dl. The X-axis shows d post infection. There was no significant difference between the median changes in haemoglobin following the 50 μg/kg/d dose (n = 14; ) than following the 75 μg/kg/d dose (n = 13; ▪) at any of the three time-points. The data in the nine paediatric patients treated with 75 μg/kg/d (n = 9; □) were similar to the data in adults.

This study demonstrates that seven out of nine children and 9 out of 13 adults had platelet increases > 20 × 109/l by the next day following infusion of 75 μg/kg/d of i.v. anti-D. The platelet counts 7 d after treatment continued to show a benefit from the 75 μg/kg/d dose (Fig 1) and there was also a substantially longer duration of treatment effect that would offset the incremental cost. Premedication with single-dose acetaminophen and prednisone is recommended to minimize adverse effects that were readily tolerable in 26 out of 27 cases. Substantial haemolysis was not seen (Gaines, 2000) and no platelet transfusions were administered.

Intravenous anti-D treatment compares favourably with i.v. Ig (Bussel et al, 1985; Tarantino et al, 1999) with a shorter infusion time (minutes), a single infusion, a much smaller donor pool size and, therefore, less risk of infection transmission, and lower cost (approximately half of an equivalent treatment with i.v. Ig). The response to 75 μg/kg/d is faster than that reported with steroids (Blanchette et al, 1994). Controlled trials are needed to determine if the overnight platelet increase following 75 μg/kg/d is indeed similar to that seen following infusion of 1 g/kg/d of i.v. Ig. If so, i.v. anti-D could be used in non-splenectomized, RhD-positive children and adults with ITP whenever i.v. Ig might currently be used to provide an immediate, substantial platelet increase (Vesely et al, 2000).

Acknowledgments

The technical support of Ginette Lanoix and the secretarial assistance of Sandra Watson are gratefully acknowledged, as are the efforts of the physicians who referred their patients and participated in this study. The work was supported in part by a clinical research grant from the Cangene Corporation, Winnipeg, Manitoba, Canada, and by the ITP Society of the Children's Blood Foundation, New York, NY, USA.

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