Treatment with alkylating agents or radiophosphorous (32P) has been shown to carry a certain leukemogenic risk in myeloproliferative disorders (MPDs), including essential thrombocytemia (ET). The ...leukemogenic risk associated to treatment with hydroxyurea in ET, on the other hand, is generally considered to be relatively low. Between 1970 and 1991, we diagnosed ET in 357 patients, who were monitored until 1996. One or several therapeutic agents had been admistered to 326 patients, including hydroxyurea (HU) in 251 (as only treatment in 201), pipobroman in 43, busulfan in 41, and32P in 40. With a median follow-up duration of 98 months, 17 patients (4.5%) had progressed to acute myeloid leukemia (AML; six cases) or myelodysplastic syndrome (MDS; 11 cases). Fourteen of these patients had received HU, as sole treatment in seven cases, and preceded or followed by other treatment in seven cases, mainly pipobroman (five cases). The remaining three leukemic progressions occurred in patients treated with 32P (two cases) and busulfan (one case). The incidence of AML and MDS after treatment, using 32P alone and 32P with other agents, busulfan alone and with other agents, HU alone and with others agents, and pipobroman alone and with other agents was 7% and 9%, 3% and 17%, 3.5% and 14%, and 0% and 16%, respectively. Thirteen of 17 patients who progressed to AML or MDS had successful cytogenetic analysis. Seven of them had rearrangements of chromosome 17 (unbalanced translocation, partial or complete deletion, isochromosome 17q) that resulted in 17p deletion. They also had a typical form of dysgranulopoiesis combining pseudo Pelger Hüet hypolobulation and vacuoles in neutrophils, and p53 mutation, as previously described in AML and MDS with 17p deletion. Those seven patients had all received HU, as the only therapeutic agent in three, and followed by pipobroman in three. The three patients who had received no HU and progressed to AML or MDS had no 17p deletion. A review of the literature found cytogenetic analysis in 35 cases of AML and MDS occurring after ET, 11 of whom had been treated with HU alone. Five of 35 patients had rearrangements that resulted in 17p deletion. Four of them had been treated with HU alone. These results show that treatment with HU alone is associated with a leukemic risk of approximately 3.5%. A high proportion of AML and MDS occurring in ET treated with HU (alone or possibly followed by pipobroman) have morphologic, cytogenetic, and molecular characteristics of the 17p− syndrome. These findings suggest that widespread and prolonged use of HU in ET may have to be reconsidered in some situations, such as asymptomatic ET.
Since the first reports demonstrating the ability of a total dose of 2 g/kg body weight (b.w.) of intravenous immunoglobulin (IVIg) to increase the platelet count in patients with autoimmune ...thrombocytopenic purpura (AITP), the optimal dose has remained controversial. We report the results of a randomized study which compared two low doses of IVIg (0.5 g/kg b.w., group A, n = 19, and 1 g/kg b.w., group B, n = 18) in 37 adults with AITP and platelet count <50 × 109/l, in preparation for surgery or in a situation with a risk of bleeding. On day 4 the proportion of responses, defined by a platelet count > 80 × 109/l and at least twice the initial platelet count, was significantly higher in the group receiving 1 g/kg b.w. (12/18 in group B versus 4/19 in group A, P = 0.005). All but one of the day 4 responders had already responded on day 3. The daily changes in the platelet count from the beginning of IVIg treatment were larger in group B, with a significant difference relative to group A on day 3 (92 × 109/l in group B versus 50 × 109/l in group A, P = 0.03) and on day 4 (106 × 109/l in group B versus 55 × 109/l in group A, P = 0.03). Patients who had not responded by day 4 subsequently received 1.5 g IVIg/kg b.w. (group A) or 1 g IVIg/kg b.w. (group B). A response was observed in 11/13 initial non‐responders in group A, and in 2/6 initial non‐responders in group B. Finally, on day 8, the proportion of responders was 78% (29/37) in the entire group and was similar in the two subgroups. In conclusion, (1) initial treatment with 1 g/kg b.w. of IVIg appeared to be more effective than 0.5 g/kg b.w. in adults with AITP; (2) infusion of a low dose of IVIg did not jeopardize the efficacy of IVIg reinfusion; (3) some adults who did not respond to 1 g IVIg/kg b.w. responded to a higher dose.
In pregnant women with antecedents of autoimmune thrombocytopenia (AITP), no predictive factor for severe fetal thrombocytopenia has been identified. We evaluated the relationships between the course ...of the maternal disease before and during pregnancy and the risk of severe fetal thrombocytopenia, in 64 pregnant women with known chronic AITP antecedents, over a 12‐year period. 28 pregnant women had undergone splenectomy before pregnancy and 17 experienced severe thrombocytopenia (< 50 × 109/l) during pregnancy (monthly determination). Eight infants presented with severe thrombocytopenia at birth (12.5%), and four in the following days (6.25%). No severe haemorrhage was observed. Severe thrombocytopenia at birth was present in 57% (CI 95% 18–90%) of the infants born to mothers with severe pregnancy‐associated thrombocytopenia and splenectomy antecedents, and in 0% (CI 95% 0–15%) of the infants born to mothers who presented none of these antecedents (P = 0.001). In thrombocytopenic mothers the infant platelet counts at birth were positively correlated to the nadir maternal platelet count during the index pregnancy (r = 0.42, P = 0.0075).
These results suggest that severe autoimmune disease is a risk factor for severe fetal thrombocytopenia, and that pregnant women with no antecedent of splenectomy nor severe thrombocytopenia during pregnancy have a very low risk of severe fetal thrombocytopenia.
We treated 10 patients who had chronic refractory idiopathic thrombocytopenic purpura (ITP) with high-dose dexamethasone (DXM, 40 mg/d for 4 sequential days every month). The interval from diagnosis ...ranged from 49 to 300 months, and patients had previously received a median of 5.5 treatments (including splenectomy in nine cases). Median platelet count was 14 x 10(9)l (range 6-26 x 10(9)/l) at the onset of DXM and eight patients had bleeding symptoms. Eight patients received at least three cycles of DXM. Five patients had a response (i.e. platelet count at least doubled and increased by > 20 x 10(9)/l), including one almost complete remission and four minor responses (MR). Of the MR, one was probably due to concurrent IVIg administration, and all four MR were transient, in spite of further cycles of DXM. In three patients DXM was a failure after three or four cycles. In two patients DXM had to be stopped after one course because of major side-effects (systemic hypertension with stroke and insulin-dependent diabetes, respectively). In our experience, high-dose DXM had a relatively limited effect in chronic refractory ITP and was associated with severe side-effects in some cases.
The authors retrospectively analyzed the initial characteristics, treatment, and clinical course in 147 patients with essential thrombocythemia (ET). Median age was 60 years and the M:F ratio was ...0.69. At diagnosis, 53 patients were asymptomatic; 50 patients had functional symptoms (mainly vasomotor disturbances); 27 patients had large vessel thrombosis; 27 patients had a bleeding diathesis; and seven patients had both bleeding and thrombosis. The platelet count ranged from 0.7 to 2.92 × 1012/I. Forty‐five of the 61 tested patients (61%) had prolonged bleeding time and/or platelet hypoaggregation. Three patients had in vitro spontaneous aggregation. No significant correlations were found between hemostatic findings and in vivo bleeding or thrombosis. The incidence of bleeding, however, was higher in patients with more than 2 × 1012/I platelets. Of 87 karyotypes performed with banding techniques, only four were abnormal. One hundred twenty‐nine patients received one or more cytoreductive agents at diagnosis or during follow‐up. Sixty patients received an antiaggregating agent. First‐line therapy was radiophosphorus (32P) in 22 patients; busulfan in 35 patients; and hydroxyurea in 72 patients. Hydroxyurea required continuous maintenance therapy and had to be changed to another treatment in 12 of the initial responders because of inadequate control of thrombocythemia. During follow‐up, 14 treated patients experienced one or several major thrombotic events. Two untreated patients also had major thrombosis. Only one major bleeding event was seen during follow‐up. Median actuarial survival was 73.5% at 7 years and only one patient progressed to acute non‐lymphocytic leukemia (ANLL). These results suggest that large vessel thrombosis is the main complication of ET. It appears largely unpredictable in a given patient at diagnosis but can be largely prevented by the control of thrombocythemia. Because of the low incidence of side effects of treatment in this experience, the authors believe that cytoreductive therapy is indicated in most patients with ET, as long as a group of patients with very low risk of thrombosis is not defined in prospective studies.
We treated 53 adults (mean age 54 years, range 17-89; 37 females and 16 males) with chronic idiopathic thrombocytopenic purpura (ITP) by azathioprine. All patients had received at least one form of ...therapy (including splenectomy in 40 patients) and had less than 50 x 10(9)/1 platelets. The duration of ITP before azathioprine was started ranged from 6 to 350 months (median 19). All patients initially received 150 mg/d of azathioprine. This was associated with a short initial course of prednisone (0.3-0.5 mg/kg d) in 10 of them, who were refractory to prednisone alone. 34 (64%) patients responded, including 24 (45%) complete remissions (CR), three (6%) partial remissions (PR) and seven (13%) minor responses (MR). Median time to achieve response was 4 months. 17 of the CR persisted after 7-182 months, 10 of them after discontinuation of azathioprine. Seven patients relapsed after 4-26 months, five of them after azathioprine was stopped or its dose was reduced. PR were short and the median duration of MR was 8 months. Overall, 21 patients (40%) had responses lasting 1 year or more and 17 (32%) lasting 2 years or more. Median duration of treatment was 18 months (range 3-84). Five patients died of bleeding while on treatment. No prognostic factors for response to azathioprine were found. Mild leucopenia was seen in seven patients and a moderate (x3) increase in transaminases in two patients. No opportunistic infections were seen and no malignancy has occurred since the onset of azathioprine. We conclude that azathioprine gives a relatively high incidence of durable responses and very limited side effects in chronic ITP, when splenectomy has failed or is contraindicated. This efficacy, in our experience, is superior to that obtained with other therapeutic approaches. As responses may be delayed, a course of azathioprine of 4 months is required before one can infer a failure to respond. In responding patients, however, the optimum duration of treatment remains to be established.
Treatment with alkylating agents or radiophosphorous (32P) has been shown to carry a certain leukemogenic risk in myeloproliferative disorders (MPDs), including essential thrombocytemia (ET). The ...leukemogenic risk associated to treatment with hydroxyurea in ET, on the other hand, is generally considered to be relatively low. Between 1970 and 1991, we diagnosed ET in 357 patients, who were monitored until 1996. One or several therapeutic agents had been administered to 326 patients, including hydroxyurea (HU) in 251 (as only treatment in 201), pipobroman in 43, busulfan in 41, and 32P in 40. With a median follow-up duration of 98 months, 17 patients (4.5%) had progressed to acute myeloid leukemia (AML; six cases) or myelodysplastic syndrome (MDS; 11 cases). Fourteen of these patients had received HU, as sole treatment in seven cases, and preceded or followed by other treatment in seven cases, mainly pipobroman (five cases). The remaining three leukemic progressions occurred in patients treated with 32P (two cases) and busulfan (one case). The incidence of AML and MDS after treatment, using 32P alone and 32P with other agents, busulfan alone and with other agents, HU alone and with others agents, and pipobroman alone and with other agents was 7% and 9%, 3% and 17%, 3.5% and 14%, and 0% and 16%, respectively. Thirteen of 17 patients who progressed to AML or MDS had successful cytogenetic analysis. Seven of them had rearrangements of chromosome 17 (unbalanced translocation, partial or complete deletion, isochromosome 17q) that resulted in 17p deletion. They also had a typical form of dysgranulopoiesis combining pseudo Pelger Hüet hypolobulation and vacuoles in neutrophils, and p53 mutation, as previously described in AML and MDS with 17p deletion. Those seven patients had all received HU, as the only therapeutic agent in three, and followed by pipobroman in three. The three patients who had received no HU and progressed to AML or MDS had no 17p deletion. A review of the literature found cytogenetic analysis in 35 cases of AML and MDS occurring after ET, 11 of whom had been treated with HU alone. Five of 35 patients had rearrangements that resulted in 17p deletion. Four of them had been treated with HU alone. These results show that treatment with HU alone is associated with a leukemic risk of approximately 3.5%. A high proportion of AML and MDS occurring in ET treated with HU (alone or possibly followed by pipobroman) have morphologic, cytogenetic, and molecular characteristics of the 17p- syndrome. These findings suggest that widespread and prolonged use of HU in ET may have to be reconsidered in some situations, such as asymptomatic ET.
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