A randomized, double-blind trial of pegfilgrastim versus filgrastim for the management of neutropenia during CHASE(R) chemotherapy for malignant lymphoma.

Pegfilgrastim is a pegylated form of the granulocyte-colony stimulating factor, filgrastim. Herein, we report the results of a multicentre, randomized, double-blind phase III trial comparing the efficacy and safety of pegfilgrastim with filgrastim in patients with malignant lymphoma. Patients were randomized to receive either a single subcutaneous dose of pegfilgrastim or daily subcutaneous doses of filgrastim on day 4 after the completion of cyclophosphamide, cytarabine, etoposide and dexamethasone ± rituximab (CHASE(R); day 1-3) chemotherapy. The primary endpoint was the duration of severe neutropenia (DSN), defined as the number of days with neutrophil count <0·5 × 10(9) /l in the first cycle of chemotherapy. A total of 111 lymphoma patients were randomized to either the pegfilgrastim or filgrastim group. 109 patients received either pegfilgrastim (n = 54) or filgrastim (n = 55). Efficacy data were available for 107 patients (pegfilgrastim: n = 53, filgrastim: n = 54). Both groups were well balanced in terms of gender, age, performance status and other variables. The mean DSN (±S.D.) was 4·5 (±1·2) and 4·7 (±1·3) d in the pegfilgrastim and filgrastim groups. No significant difference in safety was observed. This trial verified the non-inferiority of a single subcutaneous dose of pegfilgrastim compared with daily subcutaneous doses of filgrastim, considering DSN as an indicator.

Long-term outcome of patients with acquired chronic pure red cell aplasia (PRCA) following immunosuppressive therapy: a final report of the nationwide cohort study in 2004/2006 by the Japan PRCA collaborative study group.

Immunosuppressive therapy has been employed as the initial treatment for acquired chronic pure red cell aplasia (PRCA), such as idiopathic, thymoma-associated, or large granular lymphocyte (LGL) leukaemia-associated PRCA, which is thought to be immune-mediated. To explore the overall long-term outcome following immunosuppression and to identify the risk factors for death in these disorders, we conducted nationwide surveys in Japan 2004 and 2006, and identified a total of 185 patients with acquired chronic PRCA, including 72 idiopathic, 41 thymoma-associated and 14 LGL leukaemia-associated cases of PRCA for whom data was available. The present study evaluated 127 patients with these three subsets of PRCA. The median overall survival has not yet been reached in idiopathic PRCA. The estimated median overall survival times in patients with thymoma-associated and LGL leukaemia-associated PRCA were 142·1 and 147·8 months, respectively. Twenty-two deaths were reported, and the response to induction therapy and relapse of anaemia were found to be associated with death. The major causes of death were infection in seven patients and organ failure in another seven patients. The results suggest that maintenance therapy and the management of infectious complications are crucial for improving the prognosis of chronic PRCA.

Deferasirox Decreases Liver Iron Concentration in Iron-Overloaded Patients with Myelodysplastic Syndromes, Aplastic Anemia and Other Rare Anemias.

Iron overload in transfusion-dependent patients with rare anemias can be managed with chelation therapy. This study evaluated deferasirox efficacy and safety in patients with myelodysplastic syndromes (MDS), aplastic anemia (AA) or other rare anemias. A 1-year, open-label, multicenter, single-arm, phase II trial was performed with deferasirox (10­40 mg/kg/day, based on transfusion frequency and therapeutic goals), including an optional 1-year extension. The primary end point was a change in liver iron concentration (LIC) after 1 year. Secondary end points included changes in efficacy and safety parameters (including ophthalmologic assessments) overall as well as in a Japanese subpopulation. Overall, 102 patients (42 with MDS, 29 with AA and 31 with other rare anemias) were enrolled; 57 continued into the extension. Mean absolute change in LIC was ­10.9 mg Fe/g dry weight (d.w.) after 1 year (baseline: 24.5 mg Fe/g d.w.) and ­13.5 mg Fe/g d.w. after 2 years. The most common drug-related adverse event was increased serum creatinine (23.5%), predominantly in MDS patients. Four patients had suspected drug-related ophthalmologic abnormalities. Outcomes in Japanese patients were generally consistent with the overall population. Results confirm deferasirox efficacy in patients with rare anemias, including a Japanese subpopulation. The safety profile was consistent with previous studies and ophthalmologic parameters generally agreed with baseline values (EUDRACT 2006-003337-32).

Cefozopran, meropenem, or imipenem-cilastatin compared with cefepime as empirical therapy in febrile neutropenic adult patients: A multicenter prospective randomized trial.

We conducted an open-label, randomized study to evaluate the clinical efficacy of cefozopran, meropenem or imipenem-cilastatin using cefepime as a control in febrile neutropenia (FN) patients. Three hundred and seventy-six patients received cefepime, cefozopran, meropenem or imipenem-cilastatinas initial therapy for FN. The primary endpoint was the non-inferiority of response rates including modification at day 7 in cefozopran, meropenem or imipenem-cilastatin patients compared with cefepime in the per-protocol population (delta = 10%). The response rates for cefozopran, meropenem and imipenem-cilastatin were not significantly different compared with cefepime (cefozopran: 54/90 (60%), meropenem: 60/92 (65%), and IPM/CS: 63/88 (72%) versus cefepime: 56/85 (66%) (p = 0.44, 1.0 and 0.51, respectively)), and the differences in treatment success for cefozopran, meropenem and imipenem-cilastatin compared with cefepime were -5.9% (95% confidence interval (CI): -20.1-8.4), -0.7% (95% CI: -14.6-13.3), and 5.7% (95% CI: -8.1-19.4), respectively. The same tendency was seen in the modified intention-to-treat population. Based on the evaluation of initial drug efficacy performed on days 3-5, there was no significant difference between the four drugs. In the subgroup with an absolute neutrophil count ≤ 100 × 10(6)/L for longer than seven days, there was significantly better efficacy in the carbapenem arm compared to 4th generation beta-lactams (52% versus 27% at days 3-5, p = 0.006, and 76% versus 48% at day 7, p = 0.002). Our results suggest that the effects of these four drugs as empiric therapy were virtually the same for adult FN patients, although non-inferiority was shown only in imipenem-cilastatin compared with cefepime (clinical trial number: UMIN000000462).

Pregnancy and delivery in a PNH patient treated with eculizumab.

We report a 37-year-old pregnant woman with paroxysmal nocturnal hemoglobinuria (PNH) treated with eculizumab. She had been diagnosed with PNH-aplastic anemia at age 19 years, and started to receive eculizumab at age 35 years. Thereafter, she had no hemolytic attacks. She became pregnant 2 years later, and treatment with eculizumab was continued. During her pregnancy, she showed no exacerbation of hemolysis. She delivered a girl by Caesarean section at 37 weeks and 3 days of gestation. Postpartum, anticoagulant therapy was started. Although mild hemolysis and a rise in FDP/Ddimer were seen, she had no symptoms of thrombosis. Ten days after delivery, she and her baby were discharged. Eculizumab was present in the first breast milk and cord blood but was below detectable levels. The cord blood showed blockage of hemolysis.

Prospective randomized study of cefepime, panipenem, or meropenem monotherapy for patients with hematological disorders and febrile neutropenia.

The aim of this study was to evaluate the usefulness of carbapenems as initial treatment for febrile neutropenia (FN), and in patients unresponsive to this initial therapy, to evaluate the efficacy of subsequent treatment with aminoglycosides (AGs) or ciprofloxacin (CPFX). FN patients were randomized to receive cefepime (CFPM, control), panipenem/betamiprom (PAPM/BP), or meropenem (MEPM). Defervescence, an outcome endpoint, was evaluated 3 days later. Patients with minimal response were given CPFX or AGs, and their responses were reevaluated on day 7. A total of 255 patients were included. The efficacies of CFPM, PAPM/BP, and MEPM were comparable. In patients unresponsive to this initial therapy, the efficacy of subsequent CPFX and AGs treatments was also similar. There was no significant between-arm difference in cumulative efficacy on days 14 and 30. Adverse reactions were infrequent and mild. In conclusion, PAPM/BP and MEPM are as useful as CFPM as initial therapy for FN, and AGs are as efficacious as CPFX in patients unresponsive to the initial therapy.

Empirical voriconazole therapy for febrile neutropenic patients with hematological disorders: a prospective multicenter trial in Japan.

An open-label, prospective, multicenter study was conducted between October 2006 and March 2010 to assess the efficacy and safety of intravenous voriconazole (VRCZ) as empirical therapy for antibiotic-refractory febrile neutropenia in Japanese patients with hematological disorders. In addition, to find the patient groups that may benefit from antifungal therapy, the definition of invasive fungal infection proposed by EORTC/MSG (2002) was assessed in this study. Plasma (1-3)-ß-D-glucan and Aspergillus PCR in blood were also measured to improve the diagnostic accuracy. A total of 103 patients (median age, 59 years), including 25 undergoing induction chemotherapies and 19 allogeneic hematopoietic cell transplants, were evaluable. Sixty-nine percent of the patients achieved resolution of clinical symptoms and 31% achieved treatment success, defined as fulfilling the previously described five-part composite endpoint. Although VRCZ was discontinued in 9.7% of the patients because of adverse effects, all the patients recovered soon after discontinuation of VRCZ. The treatment success rate of VRCZ appeared to be higher in patients categorized as "not classified" compared with "possible invasive fungal disease" according to the EORTC/MSG criteria. Moreover, six "not classified" patients were positive for either plasma (1-3)-ß-D-glucan (n = 5) or Aspergillus PCR in blood (n = 2). The present study demonstrates that empirical VRCZ therapy is safe and effective in Japanese patients. Additionally, (1-3)-ß-D-glucan and Aspergillus PCR tests were expected to provide additional information on the diagnosis of invasive fungal infections.

Efficacy and safety of micafungin as an empirical antifungal therapy for suspected fungal infection in neutropenic patients with hematological disorders.

This prospective multicenter study was performed to clarify the efficacy and safety of micafungin (MCFG) as an empirical antifungal therapy for suspected fungal infection in patients with hematological disorders and neutropenia. Three hundred and eighty-eight patients were enrolled; 151 patients with possible fungal infection diagnosed by radiological imaging or serological testing and 237 patients with refractory fever were included in this study. The mean dose and duration of treatment with MCFG were 154.6 mg/day and 14.0 days, respectively. The clinical response rate for patients with possible fungal infection and refractory fever was 60.1% and 65.3%, respectively. Even in persistent neutropenic patients with a neutrophil count of <500/µL throughout the MCFG treatment, the clinical response rate was 46.9%. Ninety-one drug-related adverse events (DAEs) were observed in 56 patients (14.4%) and 9 serious DAEs were observed in 6 patients (1.5%). Neither daily dose nor duration of MCFG treatment affected the incidence of DAEs. It was confirmed that MCFG has adequate clinical efficacy and is safe for the treatment of suspected fungal infections in patients with hematological disorders and neutropenia.

Efficacy and safety of doripenem for sepsis with neutropenia in Japanese patients with hematologic diseases.

Doripenem (DRPM) is one of the carbapenems which has a broad-spectrum and strong activity against Pseudomonas aeruginosa. This observational study was conducted between April 2006 and March 2007 in Japan to evaluate the efficacy and safety of DRPM 0.5 g three times a day for sepsis with neutropenia in patients with hematologic diseases. One hundred-nineteen patients were enrolled from 34 medical institutes, comprising 117 patients for safety evaluation and 104 for efficacy evaluation. Monotherapy of DRPM 0.5 g three times a day (DRPM monotherapy) was evaluated in 73 patients. The response rates of DRPM monotherapy at 72 hours and at Day 7 were 31.5% (23/73) and 67.1% (49/73), respectively. The incidence of adverse reactions including abnormal changes in laboratory values was 23.1%, and hepatic toxicity was most common. All of these adverse events were judged by the investigators as non-serious and tolerable. These results suggest that DRPM is useful for sepsis with neutropenia, though further study may be warranted.

Alcohol consumption is inversely correlated with insulin resistance, independent of metabolic syndrome factors and fatty liver diseases.

BACKGROUND AND AIM: The role of alcohol consumption in insulin resistance remains unclear. The aim of this study was to examine the association between alcohol consumption and insulin resistance in a large asymptomatic population. METHODS: A total of 2463 asymptomatic Japanese men aged 28 years or above undergoing a comprehensive health checkup including an oral glucose tolerance test between May 2007 and April 2010 were recruited. Participants positive for hepatitis B or C virus, abstinent alcoholics, those taking hepatotoxic drugs, those with chronic renal or hepatic failure, and those under treatment for metabolic disorders were excluded. Fatty liver was defined ultrasonographically. Visceral and subcutaneous adipose tissues were measured with computed tomography. The homeostasis model assessment of insulin resistance (HOMA-IR) score was determined to estimate insulin resistance. The association between alcohol consumption and HOMA-IR score was investigated with multivariate regression analysis. RESULTS: A total of 1902 participants were eligible for this cross-sectional survey. A significant difference in distribution of each drinking category was noted between 249 participants with insulin resistance (HOMA-IR ≥2.5) and 1653 participants without insulin resistance (HOMA-IR <2.5; P=0.001). Light (40 to 140 g/wk), moderate (140 to 280 g/wk), and heavy alcohol consumption was inversely associated with HOMA-IR scores (coefficients=-0.125, -0.127, and -0.162; P=0.007, 0.011, and 0.006, respectively) with multivariate analysis after adjusting for potential confounding variables, including visceral and subcutaneous adipose tissues, metabolic profiles, fatty liver, and liver enzyme activities. CONCLUSIONS: Alcohol consumption was inversely associated with insulin resistance, independent of central obesity, metabolic profiles, and fatty liver diseases.

Clinical efficacy and safety of biapenem for febrile neutropenia in patients with underlying hematopoietic diseases: a multi-institutional study.

A multi-institutional study was conducted to assess efficacy and safety of biapenem (BIPM), a carbapenem antibiotic, as an initial-stage therapeutic agent for febrile neutropenia (FN) in patients with hematopoietic diseases. A total of 216 patients from 25 medical institutions were enrolled in this study; of these, 204 were included in the safety analysis and 178 in the efficacy analysis. The combined (excellent and good) response rate was 67.9%, and antipyretic effect (subsidence + tendency to subsidence) was achieved within 3 and 5 days of treatment in 67.3 and 75.9% of patients, respectively. Thus, the clinical responses were gratifying. A response rate of 61.7% (37/60) was observed even in high-risk FN patients in whom neutrophil counts prior to and at 72 h after the start of BIPM were ≤100/µl. BIPM is considered to be a highly promising drug, with prompt onset of clinical benefit, as an initial-stage therapeutic agent for the treatment of FN in patients with hematopoietic diseases.

Light and moderate alcohol consumption significantly reduces the prevalence of fatty liver in the Japanese male population.

OBJECTIVES: The effect of alcohol consumption on the liver is controversial. Recent reports have suggested that moderate alcohol consumption decreases the prevalence of elevated alanine aminotransferase levels. The role of alcohol consumption in the development of fatty liver (FL), however, has not been studied definitively. The aim of this study was to examine the association between alcohol consumption and FL in a large Japanese population. METHODS: A total of 7,431 asymptomatic male subjects who underwent a complete medical survey in our institute between May 2007 and July 2008 were recruited. Cases positive for hepatitis B or C viruses, potential hepatotoxic drug intake, or under treatment for metabolic disorders were excluded. FL was defined by ultrasonography. Visceral and subcutaneous adipose tissues (VAT and SAT) were measured by computed tomography. Independent and significant predictors associated with FL were determined by multiple logistic regression analysis. RESULTS: Of the initial study candidates, 130 (1.7%) were positive for hepatitis B and 66 (0.8%) were positive for hepatitis C. On the basis of the inclusion and exclusion criteria, 5,599 men (50.9+/-8.1 years) were studied cross-sectionally. Light (40-140 g/week) and moderate (140-280 g/week) alcohol consumption significantly and independently reduced the likelihood of FL (odds ratio=0.824 and 0.754, 95% confidence interval=0.683-0.994 and 0.612-0.928, P=0.044 and 0.008, respectively) by multivariate analysis after adjusting for potential confounding variables. VAT, SAT, low-density lipoprotein, triglycerides, and fasting blood glucose were significant predictors of the increased prevalence of FL, whereas age was a predictor of the decreased prevalence of FL. CONCLUSIONS: The prevalence of FL was significantly and independently decreased by light and moderate alcohol consumption in men of an asymptomatic Japanese population.

Acquired pure red cell aplasia associated with malignant lymphomas: a nationwide cohort study in Japan for the PRCA Collaborative Study Group.

Pure red cell aplasia (PRCA) has been reported in association with lymphoma as one of the autoimmune diseases seen during the course of lymphoid malignancies. However, the relation of PRCA with the underlying lymphomas remains unclear. The aim of this study was to clarify the histologic subtypes of lymphomas, the chronological sequence of anemia and lymphoma, and the response to treatment. We conducted a nationwide survey in Japan. From a cohort of 185 PRCA patients, 8 patients with lymphoma were evaluated. Histologic subtypes varied and the lymphoma was of the B-cell type in four cases and of the T-cell type in four. Four patients simultaneously developed PRCA and lymphoma. Three patients developed PRCA following lymphoma, two of whom developed anemia during remission of lymphoma. PRCA preceded lymphoma in one patient. Effective chemotherapy was associated with remission of anemia in concurrent lymphoma and PRCA. Overall, anemia responded to chemotherapy and/or immunosuppressive therapy in seven patients. In four responding patients, PRCA remained in durable remission without maintenance immunosuppressive therapy, which is different from a recurrent feature of idiopathic PRCA. We suggest that the mechanism of lymphoma-associated PRCA is heterogeneous and that durable maintenance-free remission of anemia can be obtained in some patients.

Helicobacter pylori infection significantly increases insulin resistance in the asymptomatic Japanese population.

BACKGROUND: Helicobacter pylori infection has been shown to contribute to atherosclerosis and cardiovascular diseases. Insulin resistance is the pathophysiologic background of the clinical features of atherosclerosis and cardiovascular diseases. We examined the association between H. pylori infection and insulin resistance in a large Japanese population. MATERIALS AND METHODS: Fifteen hundred ninety-eight consecutive asymptomatic subjects that underwent a complete medical survey in our institute between May 2007 and July 2008 were recruited. Cases under medication for hypertension, hyperlipidemia, diabetes mellitus, hyperuricemia, or cardiovascular diseases were excluded from the study. Cases suffering from chronic renal or liver failure were also excluded. The homeostasis model assessment of insulin resistance (HOMA-IR) score was used to quantitatively estimate insulin resistance. Visceral and subcutaneous adipose tissues (SAT) were measured by computed tomography. The association between H. pylori serostatus and HOMA-IR score was investigated by multivariate regression analysis. RESULTS: A total of 988 men and 119 women were eventually eligible for this cross-sectional survey. Helicobacter pylori seropositivity was significantly higher in 99 cases with insulin resistance (HOMA-IR >or=2.5) compared with 1008 cases without insulin resistance (HOMA-IR <2.5) (39.4 vs 28.7%, p = .027). There was a significant association between H. pylori serostatus and HOMA-IR score by multiple linear regression analysis (coefficients = 0.152, 95% CI = 0.058-0.246, p = .001), after adjusting for sex, age, body mass index, waist girth, visceral and subcutaneous adipose tissues, smoking status, alcohol consumption, dietary habits, and physical activity. CONCLUSIONS: Helicobacter pylori infection significantly and independently contributed to promoting insulin resistance in a large asymptomatic population.

Helicobacter pylori infection is significantly associated with metabolic syndrome in the Japanese population.

BACKGROUND: Metabolic syndrome comprises a cluster of metabolic abnormalities leading to insulin resistance and atherosclerosis, and Helicobacter pylori is thought to be a contributing factor. AIM: We examined the association between H. pylori infection and metabolic syndrome in a large Japanese population. METHOD: Consecutive asymptomatic subjects that underwent a complete medical survey in our institute between April 2006 and March 2007 were recruited, and a total of 5,488 men and 1,906 women were cross-sectionally studied. The association of H. pylori serostatus with traditional atherosclerosis risk factors was investigated by multiple linear regression analysis. Independent and significant factors affecting metabolic syndrome were determined by multiple logistic regression analysis. RESULTS: H. pylori seropositivity significantly increased with age in both men and women. H. pylori seropositivity was significantly higher in cases with metabolic syndrome compared with those without metabolic syndrome (P < 0.001). There was a significant and independent association between H. pylori seropositivity and metabolic syndrome (OR 1.39, 95% CI 1.18-1.62, P < 0.001) by multiple logistic regression analysis. H. pylori seropositivity was significantly associated with higher systolic blood pressure (beta coefficient = 1.03, P= 0.014), lower high-density lipoprotein (HDL)-cholesterol level (beta coefficient =-2.00, P < 0.001), and higher LDL-cholesterol level (beta coefficient = 2.21, P= 0.005) by multiple linear regression analysis. CONCLUSION: In a large Japanese population, H. pylori infection was significantly associated with metabolic syndrome.

Long-term response and outcome following immunosuppressive therapy in thymoma-associated pure red cell aplasia: a nationwide cohort study in Japan by the PRCA collaborative study group.

BACKGROUND: Thymoma-associated pure red cell aplasia (PRCA) accounts for a significant proportion of cases of secondary PRCA and immunosuppressive therapy has been reported to be useful in this condition. However, because of its rarity, the long-term response and relapse rates after immunosuppressive therapy are largely unknown, and optimal management of this disorder remains unclear. The aim of this study was to collect more information on the outcome of patients with thymoma-associated PRCA. DESIGN AND METHODS: We conducted a nationwide survey in Japan. From a total of 185 patients, comprising 73 with idiopathic and 112 with secondary PRCA, 41 patients with thymoma were evaluated for this report. End-points of this study were the response rate, duration of the response after immunosuppressive therapy and overall survival. RESULTS: Surgical removal of thymoma was reported in 36 patients, 16 of whom developed PRCA at a median of 80 months post-thymectomy. First remission induction therapy was effective in 19 of 20 patients treated with cyclosporine, 6 of 13 patients treated with corticosteroids and 1 of 1 treated with cyclophosphamide. No cyclosporine-responders relapsed within a median observation period of 18 months (range; 1 to 118 months). Relapse of anemia was observed in three corticosteroid-responders who did not receive additional cyclosporine. Only two patients were in remission after stopping therapy for 19 and 67 months. The estimated median overall survival time of all patients was 142 months. CONCLUSIONS: Thymoma-associated PRCA showed an excellent response to cyclosporine and cyclosporine-containing regimens were effective in preventing relapse of anemia. It does, however, remain uncertain whether cyclosporine can induce a maintenance-free hematologic response.

Long-term responses and outcomes 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.

Large granular lymphocyte leukemia-associated pure red cell aplasia accounts for a significant portion of secondary pure red cell aplasia cases. However, because of its rarity, long-term responses and relapse rates after immunosuppressive therapy are largely unknown. We conducted a nationwide survey in Japan and collected 185 evaluable patients. Fourteen patients with large granular lymphocyte leukemia-associated pure red cell aplasia were evaluated. Cyclophosphamide, cyclosporine A and prednisolone produced remissions in 6/8, 1/4 and 0/2 patients respectively. Seven and 5 patients were maintained on cyclophosphamide or cyclosporine A respectively. Two patients relapsed after stopping cyclophosphamide, and 2 patients relapsed during maintenance therapy with cyclosporine A. The median relapse-free survival in the cyclophosphamide - and the cyclosporine A groups was 53 and 123 months respectively. Large granular lymphocyte leukemia-associated pure red cell aplasia showed a good response to either cyclophosphamide or cyclosporine A. Most patients continued to receive maintenance therapy and it remains uncertain whether cyclophosphamide or cyclosporine A can induce a maintenance-free hematologic response in large granular lymphocyte leukemia-associated pure red cell aplasia.

A safety, pharmacokinetic and pharmacodynamic investigation of deferasirox (Exjade, ICL670) in patients with transfusion-dependent anemias and iron-overload: a Phase I study in Japan.

The pharmacokinetics (PK) and pharmacodynamics (PD) of the once-daily, oral ironchelating agent, deferasirox (Exjade, ICL670), have been evaluated further in a Phase I, openlabel, multicenter, dose-escalation study in Japanese patients with myelodysplastic syndromes, aplastic anemia, and other anemias. Deferasirox was initially administered as a single dose of 5 (n = 6), 10 (n = 7), 20 (n = 6) or 30 (n = 7) mg/(kg day) and then after 7 days seven daily doses were administered. Linear PK (C (max) and AUC) were observed at all doses after a single dose and at steady state, and dose-dependent iron excretion was observed. Pharmacokinetic/pharmacodynamic parameters were similar to those reported in a Caucasian beta-thalassemia cohort. Following the single- and multiple-dose phases, 21 of 26 patients progressed to a 3-year extension phase of the study, where dose reductions and increases [5-30 mg/(kg day)] were allowed following safety and efficacy assessments. In the interim, 1-year data show that deferasirox was well tolerated, with generally infrequent and mild adverse events. Reductions in serum ferritin levels were observed and a negative iron balance achieved at doses of 20-30 mg/(kg day). These data suggest that deferasirox has a stable and predictable PK/PD profile, irrespective of underlying disease or race, and a predictable and manageable safety profile suitable for chronic administration.

[Immunosuppressive therapy with antithymocyte globulin and cyclosporine for paroxysmal nocturnal hemoglobinuria].

Immunosuppressive therapy (IST) for paroxysmal nocturnal hemoglobinuria (PNH) has been infrequently reported. Four PNH cases were treated with antithymocyte globulin (ATG) at our center. We assessed and reviewed the efficacy and safety of IST for PNH. ATG therapy was performed for progression of cytopenia in 3 classical-type and 1 marrow failure-type PNH cases. ATG was administered at a dose of 15 mg/kg for 5 consecutive days. Hydration and anticoagulant therapy were given as prophylaxis for thrombosis during ATG therapy. Cyclosporine was also given to the 3 classical-type PNH patients. Three patients showed hemolytic exacerbation and thrombocytopenia during ATG administration, and all needed to receive transfusions of red blood cells and platelets; however, renal failure and thrombosis did not occur. Anemia improved in all cases within 1 year, but thereafter, recurred in 2 cases. ATG therapy is a choice of treatment for PNH, although its mechanism remains unknown.

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.

BACKGROUND AND OBJECTIVES: 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. DESIGN AND METHODS: 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. RESULTS: 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). INTERPRETATION AND CONCLUSIONS: CsA-containing regimens sustain prolonged RFS more effectively than CS in primary idiopathic PRCA and seem to be important to prevent relapse.