Nationwide Cohort Study In Japan Research Articles

Responses and Outcome Following Immunosuppressive Therapy in Large Granular Lymphocyte Leukemia-Associated Pure Red Cell Aplasia: A Nationwide Cohort Study in Japan for the PRCA Collaborative Study Group.

Background: Large granular lymphocyte (LGL) leukemia accounts for a significant part of secondary PRCA. Cyclophosphamide (CPA) therapy has been reported as being useful in the literature. However, because of its rarity, the long-term response and relapse rate after immunosuppressive therapy including CPA in LGL leukemia-associated PRCA are largely unknown, and optimal management of this disorder remains unclear.Objectives: We conducted a nationwide survey of immunosuppressive therapy for PRCA in Japan to elucidate the long-term response and overall survival (OS) of this disorder. This report is a summary focusing on CPA therapy for LGL leukemia-associated PRCA.Methods: The questionnaires were sent to 109 medical institutions in Japan to estimate the number of patients with newly diagnosed acquired PRCA. From a total of 185 patients consisting of 73 idiopathic and 112 secondary PRCA cases, we evaluated 14 patients with LGL leukemia for this report. Endpoints of this study were the response rate and the duration of the response to immunosuppressive therapy and overall survival.Results. Efficacy of the first remission induction therapy was seen in 6 out of 8 patients treated with CPA (75%), 1 out of 4 patients with cyclosporine (CsA) (25%), and 0 of 2 with corticosteroid (0%), respectively. The median initial dose of CPA for the responding patients (n=6) was 100 mg. The initial dose of CsA for the responding patient was 3.7 mg/kg. Two patients, who failed to respond to the initial CPA therapy, received CsA therapy resulting in the response in one patient. Three patients, who failed to respond to the initial CsA therapy, received CPA therapy resulting in the response in all of three patients. Two patients, who failed to respond to the initial prednisolone therapy, received CsA therapy resulting in the response in one patient. We classified the patients with LGL-associated PRCA into the CPA-group (n=9) and the CsA-group (n=3) according to the response to initial or salvage therapy. Relapse was seen in two CPA-responders following discontinuation of maintenance therapy (23, 45 months), whereas no patients relapsed on maintenance CPA therapy. The estimated median duration of the response to CPA was 125 months. The median OS has yet been reached with the median observation period of 89 months.Conclusion: CPA showed an excellent response in LGL leukemia-associated PRCA and CPA-containing regimens were effective to prevent relapse of anemia. However, most patients are still receiving CPA for maintenance therapy, and it remains uncertain whether CPA can induce maintenance-free hematological response.

Long-term outcome of patients with acquired primary idiopathic pure red cell aplasia receiving cyclosporine A. A nationwide cohort study in Japan for the PRCA Collaborative Study Group

Cyclosporine A (CsA) has become one of the leading agents for the treatment of pure red cell aplasia (PRCA). However, further studies are necessary to determine the relapse-free survival (RFS) and overall survival (OS) of patients treated with this drug, the minimum duration of therapy for induction of remission, and whether or not there is need for maintenance treatment. We conducted a nationwide survey in Japan. From a total of 185 patients (with 73 primary idiopathic PRCA and 112 with secondary PRCA), we evaluated 62 patients with primary idiopathic PRCA for this report. The remission induction therapy for these patients included CsA (n=31), corticosteroids (CS) (n=20) or other drugs (n=11). CsA and CS produced remissions in 23 (74%) and 12 (60%) patients, respectively. The salvage treatment produced remissions in 58 patients (94%). Forty-one and 15 patients were maintained on CsA+/-CS (CsA-containing group) or CS alone (CS group), respectively. The median RFS in the CsA-containing group was 103 months, longer than that seen in the CS group (33 months) (p<0.01). Of 14 patients whose CsA was discontinued, 12 patients (86%) relapsed after a median of 3 months (range 1.5 to 40 months), while only 3 of 27 patients (11%) relapsed during CsA-containing maintenance therapy. Thus, the discontinuance of maintenance therapy was strongly correlated with relapse (p<0.001). Four patients in the CsA-containing group died; however, the OS of this group was not significantly different from that of the CS-groups (p=0.104). CsA-containing regimens sustain prolonged RFS more effectively than CS in primary idiopathic PRCA and seem to be important to prevent relapse.

Responses and Outcome of Immunosuppressive Therapy in Thymoma-Associated Pure Red Cell Aplasia: A Nationwide Cohort Study in Japan for the PRCA Collaborative Study Group.

Background: Secondary pure red cell aplasia (PRCA) is associated with various underlying diseases and thymoma accounts for a significant part of secondary PRCA. Thymoma-associated PRCA is generally believed to be an organ-specific autoimmune disease as well as idiopathic form, and immunosuppressive therapy including corticosteroids (CS), cyclophosphamide (CY) and cyclosporine A (CsA) have been proven useful. However, efficacy and long-term outcome of immunosuppressive therapy for secondary PRCA could be distinct among its underlying diseases. Up to the present, the overall long-term response and relapse rates after immunosuppressive therapy in thymoma-associated PRCA are largely unknown.Objectives: We conducted a nationwide survey of immunosuppressive therapy for PRCA in Japan to elucidate the long-term relapse-free survival (RFS) and overall survival (OS) of this disorder. This report is a summary focusing on CsA therapy for thymoma-associated PRCA.Methods: The first questionnaires were sent to 109 medical centers. 273 patients were enrolled from 45 institutions. Secondary questionnaires were sent and the data on 185 patients were collected. 174 patients were eligible for further analysis and we selected 42 of 174 patients (24%) (median age, 64.5 years; range, 26 to 82 years) as thymoma-associated PRCA. Complete remission (CR), partial remission (PR) and no response (NR) were defined as the achievement of normal hemoglobin levels, the presence of anemia but with transfusion-independence and the continued presence of transfusion-dependence, respectively. RFS was estimated as transfusion-free survival without the dose escalation more than 50% of maintenance-dose. Survival was estimated by the Kaplan-Meier method and statistical difference was calculated by the generalized Wilcoxon test.Results. Surgical removal of thymoma was reported in 31 patients, and 17 patients developed PRCA after thymectomy with a median interval of 77 months (range; 1 to 366 months). Five patients underwent surgery without any immunosuppressive therapy after the diagnosis of PRCA, and no patients who achieved response were recognized. The efficacy (CR+PR) of primary treatment was seen in 19 out of 20 patients treated with CsA (95%), 6 out of 14 patients with CS (43%) and 1 of 1 with CY (100%), respectively. Relapse rates in CsA-responders and CS-responders were 0% (median observation period, 18 months) and 50% (34 months), respectively. The RFS in CsA- and CS-responders were significantly different (p=0.018). CsA-responders became independent of blood transfusion within two weeks after starting treatment. The OS did not differ substantially between the CsA- and CS-responders (p=0.663). Most CsA-responders were still on maintenance therapy, and only two patients were alive in CR after stopping therapy.Conclusion: CsA showed an excellent response in thymoma-associated PRCA. However, most patients are still receiving CsA for maintenance therapy. Therefore, other therapeutic modalities may be required to cure this disorder as is the case with idiopathic PRCA.

Long-Term Relapse-Free Survival and Overall Survival of Patients with Acquired Primary Idiopathic Pure Red Cell Aplasia Receiving Cyclosporine: A Nationwide Cohort Study in Japan for the PRCA Collaborative Study Group.

Background: The efficacy of corticosteroids (CS), cyclophosphamide (CY) and cyclosporine (CsA) for the patients with primary or secondary pure red cell aplasia (PRCA) is between 30–56%, 7–20% and 75–87%, respectively. Although it is evident that the efficacy of CsA is the highest amongst these three drugs, CsA has remained second to third-line therapy largely because the long-term relapse-free survival (RFS) and overall survival (OS) after CsA therapy are unknown.Objectives: We conducted a nationwide survey of immunosuppressive therapy for PRCA in Japan to elucidate the long-term RFS and OS of CsA therapy for acquired primary idiopathic (API-) PRCA.Methods: Questionnaires were sent to 109 medical centers. From 1990 through 2006, we identified 174 adult patients with acquired PRCA. The underlying diseases could affect RFS and OS of immunosuppressive therapy. We, therefore, selected 64 patients (38%, median age, 56 years; range, 18 to 89 years) with API-PRCA according to the classification proposed by Dessypris and Lipton. Complete remission (CR), partial remission (PR) and no response (NR) was defined as the achievement of normal hemoglobin levels, the presence of anemia but with transfusion independence, and the continued presence of transfusion dependence, respectively. RFS was estimated as transfusion free survival without the dose escalation more than 50% of maintenance-dose. Survival was estimated by the Kaplan-Meier method and statistical difference was calculated by the generalized Wilcoxon test and qui square test.Results: The efficacy (CR+PR) of primary treatment was seen in 24 of 32 patients treated with CsA (75%), 16 of 26 patients with PSL (62%), 0 of 3 patients with CY (0%), 0 of 1 patient with anabolic steroid and was undetermined in 2 patients because of short observation periods (<1 week). Overall, 60 of 64 API-PRCA patients (94%) responded to primary or subsequent immunosuppressive therapy, and 41 and 15 patients were maintained CsA±CS (CsA-responders) or CS alone (CS-responders), respectively. The median RFS in CsA-responders was 52 months and longer than that seen in CS-responders (16 months) (p<0.01), in the median follow-up period of 36 and 8 months, respectively. In CsA-responders, three patients died due to renal failure, liver failure associated with hepatitis C infection and infection after transformation to aplastic anemia. However, overall survival was not significantly different between the two groups (p=0.104). In CsA-responders, the cease of maintenance therapy was strongly correlated with relapse (p<0.001). Eleven of 14 patients relapsed with a median interval of 10 months after discontinuing CsA (range 1.5 to 40 months), whereas only 4 of 27 patients relapsed during maintenance therapy.Conclusions: We, for the first time, demonstrated that CsA ensures prolonged PFS than CS in API-PRCA. However, most patients are still receiving CsA for maintenance therapy. Therefore, other therapeutic modalities may be required to cure API-PRCA.