Long-Term Outcomes Of Combined Chemotherapy In Chronic Refractory Idiopathic Thrombocytopenic Purpura

Adult idiopathic thrombocytopenic purpura (ITP) is a chronic acquired organ-specific autoimmune hemorrhagic disease characterized by the production of auto-antibodies against antigens on the membranes of platelet, resulting in enhanced Fc-mediated destruction of the platelets by macrophages in the reticuloendothelial system.1-3 Splenectomy remains the best treatment of chronic ITP, but approximately 30% of patients do not respond or relapse after surgery;4-6 these patients are defined as patients with chronic refractory ITP. There is no consensus on an appropriate sequence of treatments for patients with chronic refractory ITP.7-9 Management of these patients remains a dilemma. We have treated 31 patients with chronic refractory ITP using low dose combination chemotherapy between 1994 and 2005, and the results are presented as follows. CLINICAL DATA Patients Between January 1, 1994 and September 30, 2005, 31 patients, aged 18 years and older, with chronic ITP who were refractory to splenectomy, were treated with a combined chemotherapy. Clinical features of these 31 patients are shown in Table 1 and the clinical manifestations included the following: purpura and petechiae (29 patients, 93.5%), epistaxis (16 patiens, 51.6%), gum bleeding (8 patients, 25.8%), hematuria (6 patients, 19.4%), excessive vaginal bleeding (8 patients, 25.8%), gastrointestinal bleeding (3 patients, 9.7%), retinal bleeding (2 patients, 6.5%) and intracerebral bleeding (2 patiens, 6.5%). All patients were treated with corticosteroids and splenectomy and an average of 5 times (range 2 to 8) of previous therapies had been unsuccessful in them. Other therapies received before combination chemotherapy included intravenous immunoglobulin in 27 patients (87.1%), vincristine in 25 (80.6%), danazol in 7 (22.6%), cyclophosphamide in 13 (41.9%), cyclosporin A in 3 (9.7%), mycophenolate mofetil in 1 (3.2%) and splenic radiation in 1 (3.2%).Table 1: Characteristics of 31 chronic refractory ITP patients in this studyAll patients failed splenectomy (platelet count after splenectomy either did not reach 30×109/L, or after an initial increase, fell below 30×109/L) and required additional therapy for symptomatic thrombocytopenia. The majority of the patients came from North China and most were hospitalized due to ineffective treatments. All patients met the diagnostic criteria reported previously.10 Detailed information regarding their diagnosis, treatment and follow-up was available in the hospital records. Patients who had not been seen recently were contacted by telephone or by mail for further follow-up information, including details of any subsequent treatment. Treatment protocols The combined chemotherapy consisted of cyclophosphamide (100-200 mg/d intravenously) on days 1 to 5 or 7 and prednisone (0.5-1.0 mg/kg orally daily) on days 1 to 7, combined with vincrinstine (1-2 mg intravenously) on day 1, and/or azathioprine (100 mg orally daily) on days 1 to 5 or 7 and/or homoharringtonine (1 to 2 mg intravenously daily) on days 1, 3, 5 or on days 1-7 and/or etoposide (50 mg orally daily) on days 1 to 7. Detailed protocols are shown in Table 2.Table 2: Response to combination chemotherapy of 31 patients in this studyThe chemotherapy was repeated about every 3 weeks, based on the number of white blood cells in peripheral blood and the depression of the bone marrow. On occasions, additional corticosteroids, intravenous gamma globulin, or platelet transfusions were given to control mucosal bleeding. Criteria of response to treatment Treatment response was defined as follows: complete response (CR), a platelet count over 100×109/L persisting for at least 2 months on no maintainence therapy; partial response (PR), platelet count within 50×109/L - 100×109/L; and no response (NR), platelet count below 50×109/L. Statistical analysis The data were analyzed by SPSS10.0 statistical software. The response to therapy was calculated by chi-square test. P value less than 0.05 was considered statistically significant. Response to therapy As shown in Table 2, 13 (41.9%) of the 31 patients had CR, 9 (29.0%) had PR, 9 (29.0%) had no response. The overall response rate to the combined chemotherapy was 71.0%. Of the 28 follow-up patients, 12 (42.9%) had CR, 7 (25.0%) had PR, 9 (32.1%) had no response. The overall response rate was 67.9%, and 10 patients with CR and 3 with PR had remissions persisted without further therapy until the last follow-up. Four of the patients had remission lasting more than 60 months, 5 more than 36 months, 1 more than 12 months and 3 less than 12 months (3, 6 and 9 months). As shown in Table 3, there was no significant correlation between response to the combined chemotherapy and gender, age, platelet count at diagnosis of ITP, platelet count before the combined chemotherapy, time from diagnosis to the combined chemotherapy as well as accessory spleen exists or not.Table 3: Factors influencing the response to combination chemotherapyMortality Of the 28 follow-up patients, 4 female patients died of bleeding from uncontrolled thrombocytopenia, and no bone marrow hypoplasia was revealed in these 4 patients. The mortality was 14.3%. Patients 11 and 19 died of gastrointestinal hemorrhage, patient 16 died of intracranial bleeding and patient 23 died of both gastrointestinal and intracranial bleeding. Patients 11, 16 and 23 had a similar clinical pattern with no persistent response to the combination chemotherapy and had frequent mucosal bleeding episodes that required multiple hospital admissions. Patient 19 initially had a partial remission after one course of CHAOP, with platelet count of 80×109-90×109/L for about one year. The platelet then decreased gradually and the patient died half a year later because of the gastrointestinal bleeding. Adverse events In general, the side effects of combination chemotherapy in the present study were minimal. No patient discontinued treatment due to severe adverse effects, including bone marrow suppression and severe constitutional symptoms. Mild nausea and vomiting, alopecia, acne and peripheral neuritis were noted in some patients. No severe infections were seen. DISCUSSION At the present, management of chronic refractory ITP remains a dilemma, principally because of the inability to balance the risk for severe bleeding against the risk for complications of treatment, given that the prognosis of individual patients with chronic refractory ITP is so variable.8 Cohen et al11 reviewed 17 case series involving 1817 patients with ITP and showed that the rate of fatal hemorrhage was between 0.0162 and 0.0389 cases per patient-year at risk (the time at risk is defined as the time during which the platelet count less than 30×109/L) and McMillan et al7 prospectively studied 114 patients with adult chronic ITP refractory to splenectomy. They came to a similar conclusion that ITP with persistent low platelet counts carried a grave prognosis. Now many agents have been proposed to treat chronic refractory ITP with some still in experimental stage, such as rituximab, campath-1H, mycophenolate mofetil, megakaryocyte growth and development factor and autologous stem cell transplantation. However, no algorithm based on evidence can be proposed for standard care of chronic refractory ITP.12 Thus, the management of chronic refractory ITP is still difficult. Figueroa et al13 in 1993 used combination chemotherapy to treat 10 patients with refractory immune thrombocytopenia. Among the 10 patients, 6 had complete responses, 2 had partial responses, and 2 had no response. McMillan14 also followed 12 patients who had prior treatment with corticosteroids and splenectomy. The chemotherapy regimen consisted of up to 6 cycles of cyclophosphamide and prednisone plus one or more other agents (vincristine, procarbazine, and/or etoposide). Initially seven patients had a CR, which was sustained in 4 patients for 60 to 150 months, and 2 had a PR. But six patients had a CR and six dead at last follow-up. In our series, we showed that 12 patients (42.9%) achieved CR, and 7 (25.0%) achieved PR until the last follow-up. Of them, 10 patients with CR and 3 with PR had remissions persisting without further therapy until the last follow-up. These included 4 patients with remissison lasting for more than 60 months, and 5 more than 36 months. Response rate (CR+PR) of the follow-up in our study was 67.9%, which is somewhat higher than that in the study of McMillan, perhaps because our follow-up time is still not sufficiently long. In general, combination chemotherapy was well tolerated without significant side effects. And no patients developed chemotherapy-induced secondary cancers during our follow-up periods. Longer term follow-up studies are needed to define the risk of secondary cancers in patients with ITP who receive chemotherapy. It is worth mentioning that patient 10 had left lower limbs deep venous thrombosis (DVT) when her platelet count was 152×109/L. Silverstein et al15 studied the trends in the incidence of deep vein thrombosis based on a 25-year population and they think the incidence of deep vein thrombosis is increasing for older women. Our patient is a 66 years old women. The old age may be responsible for her deep vein thrombosis, but not the treatment of ITP. The major cause of fatal bleeding in patients with ITP is intracranial hemorrhage.16-18 The risk of intracranial hemorrhage is greatest in the elderly, those with a history of bleeding and those without response to therapy.19,20 In our series, 4 patients died, all of bleeding caused by uncontrolled thrombocytopenia, either of central nervous system bleeding or gastrointestinal bleeding. No bone marrow aplasia or hypoplasia was revealed in these 4 patients. Among those who died, 3 patients had a similar clinical pattern: lack of persistent response to the combination chemotherapy and occurrence of frequent mucosal bleeding episodes that required multiple hospital admissions. Only one patient initialy had a PR. In our series, the mortality was lower than those reported by McMillan et al (14.3% and 50.0%, respectively). This might be due to the difference of the case choice and the follow-up time. However the mortality of two groups remains a little higher, which may be ascribed to the small case numbers. Furthermore Cortelazzo et al19 reported that at equivalent platelet count the incidence of major hemorrhagic complications was significantly higher in aged (greater than 60 years) than in younger (less than 40 years) patients. In our 4 dead patients, the age of 3 patients was over 40 years, only 1 25 years. So we think the cause of patients' death may be not due to the combination chemotherapy, but the uncontrolled decrease of the patients' platelet. In summary, approximately 67.9% of refractory ITP patients with low-dose combination chemotherapy eventually achieved a remission (CR or PR) in our study. Thus combination chemotherapy may be an effective treatment for some chronic refractory ITP patients. However, the optimal drug and the timing of the combination chemotherapy require further study. Our study would provide some valuable information for future studies. However, it did not compare with other treatments (or no treatment) in controlled trials. Thus, further research, including well designed prospective cohort studies of consecutive patients and randomized, controlled clinical trials evaluating the clinical symptoms and platelet count response, is needed to find the most optimal treatment with greater benefit/risk ratio for refractory patients to improve the response rate of refractory ITP, reducing clinically important bleeding or mortality.