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A correction has been published: N Engl J Med 1994;331(4):283.
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Background Most patients with chronic idiopathic thrombocytopenic purpura have a response to corticosteroids or intravenous immune globulin, but improvement is often transitory. Splenectomy may provide only a short-term benefit. Because pulsed high-dose therapy with potent synthetic corticosteroids is inexpensive, well tolerated, and effective in patients with secretory B-cell neoplasms, a similar regimen was examined for its efficacy in patients with chronic idiopathic thrombocytopenic purpura that was resistant to other treatments.
Methods Ten consecutively referred patients who had persistent symptomatic idiopathic thrombocytopenic purpura after undergoing at least two standard therapies were treated with six cycles of dexamethasone (40 mg per day for 4 sequential days every 28 days).
Results All patients had increased platelet counts (mean [±SD] count before treatment, 12,000 ±8200 per cubic millimeter; after treatment, 248,000 ±130,000 per cubic millimeter). The platelet counts remained above 100,000 per cubic millimeter for at least six months after the last cycle of treatment. There were no serious side effects. Features of hyperadrenocorticism due to prior corticosteroid therapy resolved during treatment. The cost of the drug was approximately $100 per patient.
Conclusions Although the possibility of spontaneous remission and a delayed benefit from prior therapy cannot be excluded in this small group of patients, pulsed high-dose treatment with dexamethasone may provide a low-cost therapeutic option with minimal side effects in patients with refractory idiopathic thrombocytopenic purpura.
Corticosteroids, the mainstay of treatment for idiopathic thrombocytopenic purpura, increase the platelet count in about 80 percent of patients given the equivalent of 1 to 2 mg of prednisone per kilogram of body weight per day9. However, many patients have a relapse when the dose of corticosteroid is reduced. Debilitating side effects are common in patients who require long-term corticosteroid therapy to maintain the platelet count. Splenectomy is usually reserved for patients who have a relapse after the withdrawal of steroids. The operation has a lasting benefit in only 50 to 70 percent of patients,9 and there are no unambiguous means of predicting success.
Intravenous gamma globulin, widely used as salvage therapy in patients with refractory idiopathic thrombocytopenic purpura or as initial therapy in those with severe disease or contraindications to steroids or splenectomy,10,11,12,13 is apparently nearly as effective as corticosteroids. However, the efficacy of intravenous gamma globulin is often short-lived. Repeated infusions may promote a lasting remission,14 but such treatment is extremely costly ($24,000 to $96,000 per course). Other treatments include vinca alkaloids,15 colchicine,16 danazol,17,18 alkylating agents,19 anti-Rho immune globulin,20 cyclosporine,21 plasmapheresis,22 and immunoadsorption apheresis on staphylococcal protein-A columns23. Short courses ("pulses") of corticosteroids in high doses (e.g., 1 to 3 g of methylprednisolone daily for four days)24 and combination chemotherapy (such as cyclophosphamide, vincristine, and prednisone)25 have also been used in refractory idiopathic thrombocytopenic purpura. These treatments are not consistently effective, however, and for patients who do not have a response to them or have not received them for medical or other reasons, a different approach is needed.
This study tested the efficacy of high-dose dexamethasone given in six cycles of limited duration (40 mg per day for 4 days every 28 days) in patients with a relapse of idiopathic thrombocytopenic purpura. This treatment was based on four considerations. No other therapy has resulted in a higher rate of initial remission or proved less costly than corticosteroids. Pulsed corticosteroids are well tolerated and effective in reducing immunoglobulin production in clonal B-cell disorders, even those refractory to other cytotoxic agents26,27,28. Dexamethasone (9
-fluoro-16-methylprednisolone) has a long half-life and minimal sodium-retaining potency, and is well-tolerated in high doses. Finally, a patient in our practice with congenital asplenia and idiopathic thrombocytopenic purpura, who had repeated relapses after steroids had been discontinued but disliked even alternate-day therapy, remained in long-term remission with a self-designed regimen of a 14-day supply of steroids taken as a single biweekly dose.
Methods
Selection of Patients
Ten consecutive outpatients who were either in our practice or referred to the Wayne State University-Detroit Medical Center Hematology and Oncology Division for treatment of resistant idiopathic thrombocytopenic purpura were enrolled in the study. All 10 had had a relapse after several therapies. Five of the patients were men, and five were women. The mean number of previous therapies per patient was 4.4 (range, 2 to 6); the mean cost of these therapies was $29,600 (range, $9,700 to $100,000).
All patients had symptomatic thrombocytopenia at the time of enrollment, five despite treatment with oral prednisone at a dose of 0.2 to 1.0 mg per kilogram of body weight per day. Symptoms included epistaxis, severe gingival bleeding, severe petechiae and ecchymoses, vaginal or gastrointestinal bleeding, and hematuria. Six of the patients had previously undergone a splenectomy; the other four had declined the procedure. Seven patients had been hospitalized for bleeding associated with thrombocytopenia within three months before enrollment in the study, but all were outpatients at the time of enrollment, and at least one month had elapsed since they had received any therapy other than prednisone.
None of the patients had diabetes or uncontrolled hypertension. None had findings suggestive of a neoplasm or risk factors for infection with the human immunodeficiency virus type 1 (HIV-1); all the male patients had negative serum tests for HIV-1 antibody. Apart from thrombocytopenia, the hemograms were negative for all 10 patients. No patient had an abnormal Westergren sedimentation rate or serologic tests suggestive of hepatitis B, hepatitis C, or a systemic autoimmune disorder. The mean platelet count was 12,000 per cubic millimeter before therapy (range, 1000 to 27,000 per cubic millimeter). The clinical and demographic characteristics of the patients at the time of enrollment are shown in Table 1.
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The patients were given 40 mg of oral dexamethasone daily for 4 days, at the beginning of each 28-day cycle. Each patient received six cycles of therapy and returned monthly thereafter for at least six months for follow-up. Five patients taking prednisone at the time of enrollment tapered and discontinued it during the first two treatment cycles. Patients were informed of possible short-term side effects of dexamethasone, such as hyperalertness, nervousness or anxiety, dysphoria, abdominal pain, and increased appetite and thirst, and were asked to contact their physician if they experienced worsening symptoms or undue discomfort. Receipt of medication was confirmed at each monthly visit.
Laboratory Studies
All patients had undergone bone marrow aspiration and biopsy at the time of the initial diagnosis. Complete hemograms were obtained at enrollment and monthly thereafter. Fasting and postprandial blood glucose levels were documented at enrollment, and fasting blood glucose levels were measured monthly thereafter, during treatment with dexamethasone. Urinalysis, stool tests for occult blood, renal and liver-function tests, serologic tests for hepatitis B and hepatitis C and for HIV-1 (in the male patients), determination of the Westergren sedimentation rate, and tests of antinuclear antibodies and anti-DNA antibodies were performed at the time of enrollment. Platelet-associated immunoglobulins (IgG and IgM) were measured, both at enrollment and on completion of treatment, by a university-based commercial reference laboratory using radiolabeled monoclonal anti-IgG and anti-IgM antibody29; the results are reported in femtomoles of IgG or IgM per platelet.
Statistical Analysis
The mean platelet concentration for the 10 patients after each cycle of treatment and three and six months after the completion of treatment was compared with the pretreatment mean value, with one-factor analysis of variance used for repeated measures. Platelet-associated immunoglobulin levels at enrollment and at six months were compared by Student's paired t-test. The platelet-associated immunoglobulin values in patients who had undergone splenectomy and in those who had not were compared with the independent t-test. Differences were considered significant at the level of P<0.05 for each statistical method.
Results
Platelet counts increased in all 10 patients after three cycles of dexamethasone treatment and continued to improve during the subsequent three cycles. The mean (±SD) count was 12,000 ±8200 per cubic millimeter before treatment and 248,000 ±130,000 per cubic millimeter after treatment. The platelet count remained above the pretreatment level in all 10 patients throughout the follow-up period, which was 12 months for 6 patients, 9 months for 1, and 6 months for 3 (Table 2 and Figure 1). As compared with the results in the patients who had undergone splenectomy, platelet counts increased more slowly but were equally sustained in patients with intact spleens (Figure 2). Neither care in our emergency department nor hospitalization was necessary for any patient during the treatment or follow-up period.
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The cost of the treatment to the patient, based on an average of retail prices at pharmacies in Detroit and its suburbs, was $16 per cycle, or $96 for a six-month course. Comparable costs for other regimens are $117 for colchicine (0.6 mg three times a day for six months), $1,482 for danazol (200 mg three times a day for six months), $550 to $800 for vincristine (2 mg monthly for six months), $50,400 for intravenous immune globulin (1 g per kilogram of body weight monthly for six months, for a 70-kg patient, at a cost of $120 per gram), $22,500 for staphylococcal protein-A immunoadsorption apheresis (nine treatments, with no special intravenous access required and no complications), and $8,500 for a splenectomy (including surgery and follow-up, a five-day hospital stay, Streptococcus pneumoniae and Haemophilus influenzae vaccines, and no complications).
Levels of platelet-associated immunoglobulins were elevated in all the patients before therapy (Table 3). All 10 patients had elevated platelet-associated IgG levels; 4 had platelet-associated IgM levels above 700 fmol per platelet. After therapy, platelet-associated IgM levels were decreased in all the patients, and platelet-associated IgG levels were decreased in all but one. However, these reductions were not significant either for the whole group or for the subgroups of patients with and without spleens.
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Ten patients with idiopathic thrombocytopenic purpura that was resistant to at least two and up to five different therapeutic regimens were treated with pulses of high-dose dexamethasone over a period of about six months. All patients had previously received prednisone; five were still receiving it at the time of enrollment. Six had not had a response to splenectomy. In all 10 patients, the platelet count increased and remained above pretreatment levels for at least six months after completion of the dexamethasone treatment. The lowest platelet count after six months of follow-up was 128,000 per cubic millimeter; in 9 of the 10 patients, the platelet count increased to more than 150,000 per cubic millimeter. All the patients continued to have adequate platelet counts (more than 100,000 per cubic millimeter) throughout the follow-up period (for at least 9 months in seven patients and at least 12 months in six) (Table 2). The responses in patients who had not undergone a splenectomy were slower and of lower magnitude but no less durable than the responses in patients who had undergone the procedure. Platelet-associated immunoglobulin levels, which were increased in all 10 patients before treatment, fell after treatment. The importance of the quantity and isotype of platelet-surface immunoglobulin in chronic idiopathic thrombocytopenic purpura is controversial, but the consistent elevation of platelet-surface IgG levels before therapy and their reduction with effective therapy in our patients suggest at least a circumstantial association with disease activity.
Although the number of patients in this study was small and patients with severe disease (requiring hospitalization, platelet transfusion, and combination chemotherapy) were excluded,25 the results suggest that familiar agents employed in novel dose schedules may be effective in treating apparently resistant idiopathic thrombocytopenic purpura30. Moreover, a lasting benefit was achieved with repetitive short bursts of high-dose corticosteroid therapy over a relatively brief period. Pulsed dexamethasone therapy did not cause persistent side effects; on the contrary, it allowed recovery from the effects of long-term administration of prednisone. Similarly, therapy with pulsed cyclophosphamide has proved both effective and less hazardous than daily therapy in patients with lupus nephritis31.
Pulsed dexamethasone therapy may not prove effective or tolerable for all patients with symptomatic idiopathic thrombocytopenic purpura, given the wide age range of patients with the disease and the variety of coexisting medical conditions that may complicate the clinical picture. The treatment is clearly inappropriate in patients with previously documented steroid-induced psychosis.
It is uncertain that the responses in these patients were independent of the therapies they had previously received32. Although at least one month had elapsed since prior treatment, except for prednisone, the improvement attributed to pulsed dexamethasone may have been partly the result of a delayed or subclinical response to the previous treatment. This concern is inherent in virtually all clinical studies of resistant disease in which patients are used as their own controls. Nevertheless, pulsed, high-dose dexamethasone provides an inexpensive, well-tolerated alternative to splenectomy and to more toxic or expensive medical treatments for patients with idiopathic thrombocytopenic purpura who have had inadequate responses to conventional therapies. This approach seems worthy of wider examination as a treatment for resistant disease and should be compared with conventional treatments for newly diagnosed symptomatic disease.
I am indebted to William A. Berk, M.D., for expert assistance with the figures, as well as helpful comments on the manuscript.
Source Information
From the Divison of Hematology and Oncology, Department of Internal Medicine, Wayne State University School of Medicine and Harper Hospital, Detroit.
Address reprint requests to Dr. Andersen at 403 Violet S., Harper Hospital, 3990 John R St., Detroit, MI 48201.
References
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Related Letters:
High-Dose Pulsed Dexamethasone for Immune Thrombocytopenia
Demiroglu H., Dündar S., Andersen J. C.
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Full Text
N Engl J Med 1997;
337:425-427, Aug 7, 1997.
Correspondence
This article has been cited by other articles:
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