Recombinant human erythropoietin in the anemia associated with multiple myeloma or non-Hodgkin's lymphoma: dose finding and identification of predictors of response.

Previous phase I-II clinical trials have shown that recombinant human erythropoietin (rHuEpo) can ameliorate anemia in a portion of patients with multiple myeloma (MM) and non-Hodgkin's lymphoma (NHL). Therefore, we performed a randomized controlled multicenter study to define the optimal initial dosage and to identify predictors of response to rHuEpo. A total of 146 patients who had hemoglobin (Hb) levels < or = 11 g/dL and who had no need for transfusion at the time of enrollment entered this trial. Patients were randomized to receive 1,000 U (n = 31), 2,000 U (n = 29), 5,000 U (n = 31), or 10,000 U (n = 26) of rHuEpo daily subcutaneously for 8 weeks or to receive no therapy (n = 29). Of the patients, 84 suffered from MM and 62 from low- to intermediate-grade NHL, including chronic lymphocytic leukemia; 116 of 146 (79%) received chemotherapy during the study. The mean baseline Hb level was 9.4 +/- 1.0 g/dL. The median serum Epo level was 32 mU/mL, and endogenous Epo production was found to be defective in 77% of the patients, as judged by a value for the ratio of observed-to-predicted serum Epo levels (O/P ratio) of < or = 0.9. An intention-to-treat analysis was performed to evaluate treatment efficacy. The median average increase in Hb levels per week was 0.04 g/dL in the control group and -0.04 (P = .57), 0.22 (P = .05), 0.43 (P = .01), and 0.58 (P = .0001) g/dL in the 1,000 U, 2,000 U, 5,000 U, and 10,000 U groups, respectively (P values versus control). The probability of response (delta Hb > or = 2 g/dL) increased steadily and, after 8 weeks, reached 31% (2,000 U), 61% (5,000 U), and 62% (10,000 U), respectively. Regression analysis using Cox's proportional hazard model and classification and regression tree analysis showed that serum Epo levels and the O/P ratio were the most important factors predicting response in patients receiving 5,000 or 10,000 U. Approximately three quarters of patients presenting with Epo levels inappropriately low for the degree of anemia responded to rHuEpo, whereas only one quarter of those with adequate Epo levels did so. Classification and regression tree analysis also showed that doses of 2,000 U daily were effective in patients with an average platelet count greater than 150 x 10(9)/L. About 50% of these patients are expected to respond to rHuEpo. Thus, rHuEpo was safe and effective in ameliorating the anemia of MM and NHL patients who showed defective endogenous Epo production. From a practical point of view, we conclude that the decision to use rHuEpo in an individual anemic patient with MM or NHL should be based on serum Epo levels, whereas the choice of the initial dosage should be based on residual marrow function.

Erythropoietin treatment of idiopathic myelofibrosis.

BACKGROUND: In order to determine whether recombinant human erythropoietin (rHuEPO) may play a role in treating anemia in idiopathic myelofibrosis (IMF), a pilot study using high doses of rHuEPO was conducted on patients with IMF. METHODS AND RESULTS: From September, 1990 to December, 1992, 7 patients (6 males and 1 female, median age 68 years) affected by IMF entered the trial. RHuEPO was administered subcutaneously 5 days a week at a dosage of 160 U/kg daily for three months. Out of 7 patients, 4 obtained a response. These responders received additional maintenance treatment with rHuEPO until relapse. Response duration was 6, 7, 10+, and 16 months, respectively. Treatment was well-tolerated. CONCLUSIONS: Our data suggest that rHuEPO may play a role in the treatment of anemia in some IMF patients.

Clinical and biological effects of erythropoietin treatment of myelodysplastic syndrome.

To evaluate its clinical efficacy as well as its biologic safety, human recombinant Erythropoietin (rh-Epo) was given to 19 patients with myelodysplastic syndromes (MDS) in an open non-randomized study. Among the seventeen evaluable patients only two showed an apparent hematologic response to rh-Epo treatment. In these patients hemoglobin levels increased from a mean pretreatment value of 8.5 and 8.4 g/dl up to 11.7 and 11.3 g/dl respectively and remained relatively stable for several weeks. In one of these patients the transfusion requirement decreased from 4 to 1.5 units per month whereas the other had no transfusion requirement during the whole period of rh-Epo treatment. Interestingly, when the responding patients, after a "wash-out" period of at least ten weeks, received an additional course of rh-Epo results were less impressive. Before treatment the serum level of endogenous Epo was 18 and 110 mU/ml in the two responding patients, whereas a mean value of 532 mU/ml (range 17-2797 mU/ml) was observed in non responders. The treatment of MDS patients with rh-Epo was clinically well tolerated since no relevant side effects were registered. Moreover, no evidence of harmful cytogenetic changes nor activation of myeloid growth factor genes, as determined by Northern blot analysis of GM-CSF and G-CSF gene expression, could be related to rh-Epo treatment. Overall, it appears that administration of rh-Epo is well tolerated but the therapeutic effects appear to be restricted to a minority of patients and a limited period of time.

Evaluation of erythroid marrow response to recombinant human erythropoietin in patients with cancer anaemia.

BACKGROUND: Anaemia is a frequent finding in patients with cancer and may be due to different causes, including blunted erythropoietin production. MATERIALS AND METHODS: In a pilot study, we administered recombinant human erythropoietin (rHuEPO) to twelve patients with solid tumours and secondary anaemia. rHuEPO was given subcutaneously 5 d per week at escalating doses (75 to 150 U/kg per day): the aim of treatment was a Hb level > or = 10 g/dl without blood transfusion. We evaluated endogenous EPO production through serum EPO levels and erythroid marrow activity by means of serum transferrin receptor (TfR). RESULTS: Six out of 12 subjects had defective endogenous EPO production. All patients but two responded to treatment with steady increases in Hb levels above 10 g/dl, and the median dose of rHuEPO required for correction of anaemia was 75 U/kg. Response was associated with an early increase in serum TfR. Six patients developed functional iron deficiency and required iron supplementation to obtain response. Treatment improved functional ability in 4/10 responders. CONCLUSIONS: Subcutaneous rHuEPO can stimulate erythroid marrow activity in cancer anaemia, even in patients with advanced disease, and marrow response can be adequately monitored by serum TfR. Functional iron deficiency as a cause of nonresponse to rHuEPO is frequent in these patients and may require parenteral iron administration. Although erythropoietin can improve the anaemia of cancer, the decision to treat should be individualised for each patient, looking more at the quality of life and cost-effectiveness than at cosmetic increases in the haemoglobin level.

[Comparative study of defibrotide and calcium heparin in the prevention of postoperative deep venous thrombosis. A randomized multicenter study]. / Studio di confronto defibrotide-eparina calcica nella profilassi della trombosi venosa profonda post-operatoria. Studio multicentrico randomizzato.

The efficacy and tolerability of defibrotide (800 mg/i.v.) and calcium heparin (15,000 UI/s.c.) in the prophylaxis of post-surgical deep venous thrombosis (DVT) and pulmonary embolism (PE) were compared in a multicentre trial involving 60 Italian surgical institutions (general surgery, obstetrics and gynecology, urology). Total enrollment was 2,250 patients (defibrotide: 1.194; calcium heparin 1.056). According to the protocol, the clinical suspicion of DVT and/or PE led to in-depth diagnostic evaluations (DVT: Doppler ultrasound velocimetry; PE: chest X-rays; ECG, pulmonary scintigraphic scanning). The incidence of post-surgical DVT was similar in the two groups (defibrotide: 8 patients; calcium heparin: 10 patients). A trend towards a lower incidence of DVT in the defibrotide group no PE; calcium heparin: 4 cases (chi 2 = 4.530, p less than 0.05). The local and systemic tolerability of both treatment was excellent. This trial, carried out in routine surgical practice, establishes the profibrinolytic approach to DVT prophylaxis as a sound and effective alternative to the traditional interference with the coagulation cascade.