BLOOD, 15 MARCH 2002 VOLUME 99, NUMBER 6
anti-D treatment and, in particular, which patients would improve their counts sufficiently to discontinue therapy and avoid splenectomy.
Patients and methods
Twenty-eight patients, including 7 men and 21 women, were enrolled between May 1996 and March 1999 from the 31 eligible patients referred for this institutional review board–approved study at the Platelet Disorders Center at the New York Presbyterian Hospital; 3 patients declined to participate. Patients were eligible if they had been diagnosed within the last year (but not within the last month) with primary ITP; had no history or findings suggestive of human immunodeficiency virus; had platelet counts 30 3 109/L (30 000/mL) or below at study entry; were Rh1; and had not undergone splenectomy. All eligible patients were invited to participate, including patients with profound thrombocytopenia and those with active bleeding. Patients were not excluded on the basis of previous treatment, and if on prednisone at the time of study this was quickly tapered. Patients also had to be appropriate candidates for splenectomy. After their initial treatment and 1-week follow-up at the New York Presbyterian Hospital, most patients were managed by their referring hematologists.
Patients were randomized for their initial treatment to receive either 50 mg/kg or 75 mg/kg of anti-D (WinRho SDF; Cangene, Winnipeg, MB). The data describing the acute platelet increases and hemoglobin decreases of these 2 doses have been reported separately.19 There was no distinction in the dose effect on the outcome of this study, and it is not therefore used or analyzed here. Subsequent to the initial infusion, patients received 50 to 75 mg/kg for each treatment, rounded off to the nearest multiple of 300 mg.
Treatment was administered whenever the platelet count was 30 3 109/ L (30 000/mL) or below. If patients maintained a stable platelet count above 30 3 109/L (30 000/mL) for more than 4 weeks and then had a single count between 20 3 109/L to 30 3 109/L (20 000-30 000/mL) in the absence of bleeding symptoms, treatment might not be administered at the discretion of the investigator provided that a subsequent count was 30 3 109/L (30 000/mL) or more.
Complete blood counts with platelet counts were obtained on days 0, 1, 7, 14, and 21 of therapy for the first infusion and weekly thereafter. The interval between these counts was extended to every 2 to 4 weeks in patients maintaining stable platelet counts. Plasma levels of glycocalicin20 and soluble CD16 (sCD16) levels21 were measured using an ELISA technique as previously described, prior to the first infusion in 17 and 22 patients, respectively. Twenty-five patients were assessed for their CDE rhesus phenotype to estimate the number of D sites on their red cells.22
Patients could receive IV anti-D for up to 1 year as part of the study. They were seen as clinically indicated and at least monthly for the first 12 months and at 3- to 6-month intervals until March 2001, until they underwent splenectomy, or until they were lost to follow-up.
Patients were assessed for signs of bleeding at their clinic visits and completed weekly diaries of their bleeding symptoms during the study period. In addition, they answered a series of specific questions at baseline, 6, 12, and 18 months aimed at determining their change in quality of life during the period of the study.
The questions analyzed were as follows: (1) I am as healthy as anybody I know. (2) Compared to 1 year ago, how would you rate your health in general now? (3) During the past 4 weeks, how much of the time did you have a lot of energy? (4) During the past 4 weeks, how much of the time did you feel tired? (5) During the past 4 weeks, to what extent has your physical health or emotional problems interfered with your normal social activities with family and friends? (6) During the past 4 weeks, how much of the time did you feel full of pep?
Acute response to anti-D was defined as a platelet increment of 20 3 109/L (20 000/mL) or more to a count above 30 3 109/L (30 000/mL) within 7 days of treatment. Responders were continued on intermittent IV anti-D as needed but were given the option of alternative therapy including splenec- tomy throughout the study. Patients who did not respond were offered
AVOIDANCE OF SPLENECTOMY WITH ANTI-D IN ITP
alternative therapy including splenectomy. Patients were considered “off treatment” if they maintained a platelet count above 30 3 109/L (30 000/ mL) without treatment for at least 6 months.
Patients were classified depending on their treatment status as of their last clinic visit. Group A includes patients who were considered off treatment. Group B includes patients who received treatment within 6 months of their last visit. This group included patients who (1) continued to receive anti-D; (2) received medication for their ITP other than anti-D, such as IVIG, prednisone, or danazol; and (3) received medication for other medical conditions that could have affected their platelet count. Group C includes patients who underwent splenectomy.
Cost analysis for the period of this study was performed assuming the average cost of anti-D as $80 per 300-mg vial and the average cost of splenectomy as $16 000.23 The actual number of vials used per patient was used in the calculations.
The mean, median, SD, and range were used to describe baseline variables, including age at study entry, months of ITP diagnosis, platelet counts before and after treatment, duration of response to treatment, posttreatment hemoglobin change, and initial mean corpuscular volume (MCV). The differences between the 3 outcome groups for these parameters were analyzed using the Kruskal-Wallis test and Mann-Whitney U test. The paired t test was used to assess the difference between the number of infusions of anti-D received before and after 12 months on study and to compare the health survey questions at 6, 12, and 18 months when compared with baseline. Relationships between the biologic variables were assessed using the Spearman rank correlation coefficient.
Patients were a median age of 28.5 years (range, 18-63 years) and a median of 3.5 months (range, 1-11 months) from their diagnosis of ITP at study initiation. As of March 2001, there was a median 26 months (range, 6-54 months) follow-up on study. Prior to study entry, 26 of the 28 patients had received a course of steroids; 15 had received IVIG; 4, danazol; 3, high-dose dexamethasone; and 6, IV anti-D. Fourteen patients had previously received both IVIG and steroids. Only 1 patient had received no previous ITP therapy.
Twelve-month interim outcome
Patients were classified into the outcome groups described in “Patients and methods.” The percentage of patients in each outcome group for the first 12 months of the study is shown in Figure 1. In summary, 26 (93%) of 28 patients responded to their initial infusion of IV anti-D (increase 20 3 109/L [20 000/mL] or more to a level above 30 3 109/L [30 000/mL]). Nineteen (68%) repeatedly responded with their platelet counts being maintained above 30 3 109/L (30 000/mL) on intermittent infusions of IV anti-D alone. Three of these 19 discontinued anti-D before the 12-month follow-up point for reasons unrelated to their platelet count. One developed breast cancer and received chemotherapy (patient no. 11, Figure 2), 1 elected to undergo splenectomy after 9 months despite continuing to respond to anti-D (no. 24), and 1 was lost to follow-up at 10 months (no. 16). Five of the 19 improved sufficiently to discontinue treatment, and 11 were still receiving intermittent doses of IV anti-D at 12 months. Of the 9 patients who could not be maintained on IV anti-D alone, 1 could not tolerate IV anti-D due to persistent anemia and repeated chill reactions despite premedication (no. 10), 2 did not respond to their first infusion, and