Recombinant human erythropoietin in transfusion-dependent anemic patients with multiple myeloma and non-Hodgkin's lymphoma--a randomized multicenter study. The European Study Group of Erythropoietin (Epoetin Beta) Treatment in Multiple Myeloma and Non-Hodgkin's Lymphoma.

One hundred twenty-one anemic, transfusion-dependent patients with multiple myeloma (MM) or low-grade non-Hodgkin's lymphoma (NHL) were randomly allocated to receive (a) recombinant human erythropoietin (rhEPO) 10,000 U/d subcutaneously 7 days a week (fixed dose group) (n = 38), or (b) rhEPO 2,000 U/d subcutaneously for 8 weeks followed by step-wise escalation of the rhEPO dose (titration group) (n = 44), or (c) no rhEPO therapy (control group) (n = 39). The total treatment period was 24 weeks. There were no differences between the three groups with regard to baseline clinical, demographic, or health status measures. The cumulative response frequency, defined as elimination of the transfusion need in combination with an increase in the hemoglobin concentration by >20 g/L, was 60% in both rhEPO treatment groups and 24% in the control group (P = .01 and .02, respectively, log rank test). For patients in the titration group the response rate on the first dose level (2,000 U/d) was only 14%. Cox's univariate regression analysis revealed that an inadequately low endogenous erythropoietin concentration in relation to the degree of anemia and a baseline platelet concentration > or = 100 x 10(9)/L were significant predictors for response to rhEPO therapy (P < .01). Multivariate regression analysis showed that relative erythropoietin concentration was the most important factor and the platelet count had no additional influence on response. Treatment with rhEPO was well tolerated. We conclude that treatment with rhEPO may be indicated in anemic MM and NHL patients with a relative erythropoietin deficiency. An initial dose of 5,000 U/d subcutaneously may be recommended.

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.

The German CML study, comparison of busulfan vs. hydroxyurea vs. interferon alpha and establishment of prognostic score 1.

From July 1983 to January 1991 a total of 622 patients were randomized (585 eligible) to compare the effects of hydroxyurea, interferon alpha (IFN), and busulfan on the duration of chronic phase, and survival. Further goals included the determination of prognostic parameters. 598 CML patients were documented and 575 evaluable. The Ph-status was known for 547 patients. 89.4% of the patients were Ph-positive (+). 11% had additional chromosome aberrations. The median survival of Ph+ patients by now is 4.2 years, that of Ph-patients 1.4 years. Ph-negative patients are older, tend to have lower cell counts and, as a group are more ill at diagnosis. A survival difference of about one year is expected between busulfan and hydroxyurea treated patients. Prospectively evaluated age, organomegaly related symptoms, Karnofsky index, extramedullary manifestations, number of erythroblasts and percent of circulating blasts proved to be of prognostic significance. A prognostic score (score 1) was determined which was superior to Sokal's score in the study population. 164 patients were randomized to receive IFN. In 54 patients (33%) IFN had to be terminated because of adverse effects, therapy resistance or other reasons. Clinically relevant neutralizing antibodies were detected in 9 cases. Most frequent adverse events were flu-like symptoms in 74%, gastrointestinal symptoms in 52%, and neurologic-psychiatric symptoms in 30% of patients. Reduction of the Ph-chromosome was observed in 13% of evaluable patients (10 of 75). In 4 patients complete cytogenetic remissions were observed, in three of these ongoing. Cytogenetic responders have a survival advantage. Interferon treated Philadelphia-negative CML patients have no survival disadvantage. The study is expected to allow statements as to the advantages or disadvantages of the use of busulfan, hydroxyurea and IFN in the treatment of CML as well as to the reliability of prognostic markers.

Chronic myelogenous leukemia: recent developments in prognostic evaluation and chemotherapy. The German CML Study Group.

Recent developments in CML research are illustrated by the results of one large randomized multicenter study carried out by the German CML Study Group. From July 1983 to January 1991, a total of 703 CML patients were recruited; 624 patients were randomized to compare hydroxyurea and interferon alpha (IFN) with busulfan. The median survival of Ph+ patients by now is 3.95 years, that of Ph- patients 1.1 years. Some difference in survival is recognizable between the treatment arms, but this is not yet significant. Fewer adverse effects are being observed in the hydroxyurea group. Ph-negative patients tend to have lower white blood cell and platelet counts. Patients (164) were randomized to receive IFN. In 50 patients (30%) IFN had to be terminated because of adverse effects, therapy resistance, or other reasons. Reduction of the Ph-chromosome was observed in 20% of evaluable patients. In 3 patients complete cytogenetic remissions were observed. Clinically relevant neutralizing antibodies were detected in 9 cases. Prospectively evaluated age, organomegaly related symptoms, Karnofsky index, extramedullary manifestations, erythroblasts, and percent of circulating blasts proved to be of prognostic significance. A prognostic score (score 1) was determined and compared to Sokal's score. It is expected that the study results will allow statements as to the advantages or disadvantages of the use of busulfan, hydroxyurea and IFN in the treatment of CML as well as to the reliability of prognostic markers.

Phase II study of pirarubicin in metastatic breast cancer.

Pirarubicin is a more lipophilic derivative of doxorubicin, with a higher uptake rate of cells, lower cardiotoxicity and better antitumor efficacy in preclinical models. Thirty-four patients with metastatic breast cancer were treated in a multicenter phase II study with pirarubicin (THP) using a dosage of 75 mg/m2/every 3 weeks. The patients had a median age of 56 years (range 41-73) and a performance status of WHO grade 0-2. Patients pretreated with anthracyclines, or who were older than 75 years and without sufficient bone marrow reserve were excluded. The 32 evaluable patients received a median number of 4 cycles (range 2-8). The myelosuppression was dose-limiting and led to infections (grades 1 and 2) in 5 patients. Twenty-eight patients developed leukocytopenia grade 3 and 4 toxicity and 7 patients experienced thrombocytopenia grade 1 and 2. The drug was subjectively well tolerated and nausea, vomiting and alopecia were mild. One complete remission with a duration of 15.4 months (67 weeks) and 7 partial remissions with a median duration of 9.3 months (40 weeks) were achieved, which resulted in an overall response rate of 25%. Twenty-one patients were stable for 17 weeks (median) under the treatment with pirarubicin.

Randomized study on the treatment of chronic myeloid leukemia (CML) in chronic phase with busulfan versus hydroxyurea versus interferon-alpha.

For palliative therapy during the chronic phase of CML busulfan has proved to be the drug of choice. During the past years hydroxyurea and also interferon-alpha have gained increasing significance since they might prolong the duration of the chronic phase. In a multicenter study it is being determined, whether the use of hydroxyurea or of interferon-alpha instead of busulfan prolongs the duration of the chronic phase of Philadelphia positive CML. Additional goals are the examination of whether the types of disease evolution and the terminal phases differ between the treatment groups, and the prospective recognition of prognostic criteria for the duration of the chronic phase of CML. By December 31, 1987, 326 CML-patients had been randomized, 150 for busulfan, 150 for hydroxyurea and 26 for interferon-alpha. The average age is 50 years. 59 patients reached the end of the chronic phase, 55 died. The mean observation time of all patients is 1.34 years. At present no significant difference in survival is recognizable between the busulfan and hydroxyurea groups. Fewer adverse effects have been observed in the hydroxyurea group. Philadelphia chromosome negative patients show a higher average age and tend to have lower white blood cell and platelet counts. The number of patients having received interferon-alpha is still too small to allow evaluation. This report intends to document organization and progress of this study which to our knowledge is, at present, the largest ongoing prospective multicenter study on the therapy of CML.

[Chemotherapy of chronic myelocytic leukemia. Status of the German Multicenter Study on busulfan versus hydroxyurea versus alpha interferon, October 1897]. / Chemotherapie der CML. Stand der deutschen Multicenter-Studie Busulfan versus Hydroxyurea versus Interferon-alpha, Oktober 1987.

For palliative therapy during the chronic phase of CML busulfan has proved to be the drug of choice. During the past years hydroxyurea and also interferon-alpha have gained increasing significance since they might prolong the duration of the chronic phase. In a multicenter study it is being determined, whether the use of hydroxyurea or of interferon-alpha instead of busulfan prolongs the duration of the chronic phase of Philadelphia-positive CML. Additional goals are the examination, whether the types of disease evolution and the terminal phases differ between the treatment groups, and the prospective recognition of prognostic criteria for the duration of the chronic phase of CML. By November 26, 1987, 321 CML-patients had been randomized, 147 for busulfan, 149 for hydroxyurea and 25 for interferon-alpha. The average age is about 50 years. 59 patients reached the end of the chronic phase, 55 died. The mean observation time of all patients is 1.34 years. At present no significant difference in survival is recognizable between the busulfan and hydroxyurea groups. Fewer adverse effects have been observed in the hydroxyurea group. Philadelphia chromosome-negative patients show a higher average age and tend to have lower white blood cell and platelet counts. The number of patients having received interferon-alpha is still too small to allow evaluation. This report intends to document organization and progress of this study which to our knowledge is, at present, the largest ongoing prospective multicenter study on the therapy of CML.

[Alpha interferon in the therapy of hairy cell leukemia. Results of 3 prospective multicenter studies in West Germany]. / Interferon alpha für die Therapie der HCL. Ergebnisse von drei Prospektiven multizentrischer Studien in der Bundesrepublik.

Within 19 months of recruitment 51 centers enrolled 84 patients in our prospective multicenter trial for low-dose IFN alpha-2c for HCL (1.2 x 10 IU/m x 28 days s.c.- or lower). Induction therapy of 84 days was followed by maintenance with 2 weekly doses. Patients who reached stage Jansen I or A were then randomized to 2 arms either to receive further IFN or to stop treatment. Reinduction was reinstituted whenever any patient lost Jansen stage A or I. Only 3 patients failed. But enrollment was discontinued when it became apparent that fatalities in splenectomized (SX) patients due to septicemia outnumbered deaths given in the literature. Low-dose IFN administered daily might compromise host defense. Our next study aimed at improving the safety of IFN for SX patients. Pulsatile IFN on 7 consecutive days within a 28-day period was given to all SX patients. A randomization of non-SX patients either to receive daily or pulsatile IFN should provide proof of the efficiency. The intermissions ought to be as suitable for in-vitro investigations as for observations concerning the capacity of IFN to produce 'induction of inducers'. Pulsatile treatment has so far been safe in 13 splenectomized patients. Central diagnostic procedures remained the same during both studies. It seems important to us to use an intermittent schedule for the injection of IFN in SX patients and to restrict splenectomy to selected patients.

Current results of a multicenter trial in multiple myeloma.

257 untreated myeloma patients (stage II and III) were studied in a multicenter trial. The patients were randomized and received MP or VCMP therapy. No differences in remission rate could be found in both therapy arms. After successful remission induction those patients without maintenance therapy relapsed significantly earlier than those patients receiving maintenance therapy. In pilot studies an etoposide therapy was found ineffective and a multidrug therapy (VBAMDex) could induce high remission rates in high risk and pretreated patients.

Antigens and circulating immune complexes related to the primate retroviral glycoprotein SiSVgp70. Indicators of early mortality in human acute leukemias and chronic myelogenous leukemias in blast crisis.

Human sera contain antigens and also circulating immune complexes that are related to the primate retroviral envelope glycoprotein gp70 of simian sarcoma/simian sarcoma associated virus (SiSV) and of gibbon ape leukemia virus (GaLV). SiSVgp70 related antigens (AG) and immune complexes (IC) are detected both in leukemic and in nonleukemic sera. In a further analysis of these data, the prognostic significance of SiSVgp70 related AG and IC in leukemic patients was examined. The data show that the presence of SiSVgp70 related AG and IC indicates an unfavorable clinical course and a shorter survival time in acute leukemias (AL) and in chronic myelogenous leukemia in blast crisis (CML-BC). Survival data of 56 of 64 patients tested were analyzed (38 patients with AL and 18 patients with CML-BC). Patients with AL whose sera were positive for SiSVgp70 related AG and IC had a median survival time of 9.5 months after diagnosis versus 16 months for patients negative for such AG and IC. This difference in survival time was more pronounced for patients with acute nonlymphocytic leukemia (ANLL) (6.5 versus 19 months). The difference in survival between SiSVgp70 related AG- and IC-negative and positive groups as tested by life table analysis (log-rank test) is significant (P less than 0.05). Patients with AL of the AG- and/or IC-positive group had fewer complete remissions. Patients who had no remissions belong to the AG- and/or IC-positive group (P = 0.06). Patients with CML-BC whose sera were positive for SiSVgp70 related AG and/or IC had a median survival time of 2 months after diagnosis versus 7 months for patients with sera negative for such AG and IC. As tested by log-rank test, survival curves between the two groups are significantly different (P less than 0.05). These findings suggest that SiSVgp70 related AG and IC may play an important role in the course of acute leukemia and can provide useful prognostic information.

[Erythropoietin assay. Comparison of a biological test system with an haemagglutination inhibition test (author's transl)]. / Nachweis von Erythropoietin. Vergleich eines biologischen Verfahrens mit einem Haemagglutinations-Hemmtest.

The results from a biological test for erythropoietin (using the rate of iron absorption in polycythemic mice) and a commercially-available immunological test (haemagglutination-inhibition test) were compared. Of 19 batches of the immunological test which were investigated, 7 batches were completely inactive and a further 3 batches reacted only with the test serum supplied with the test. There was a poor correlation between the results from the biological and the immunological measurements, both on patients with high and those with low serum erythropoietin levels. The difficulty of the immunological erythropoietin test is that pure erythropoietin is not sufficiently available. The immunological test investigated here does not use pure erythropoietin. Aside from this, pathophysiological considerations would lead one to expect basic differences between the results from immunological and biological tests.

[Long-term cultures in polycythaemia vera as proof for dependence on erythropoietin (author's transl)]. / Langzeitkulturen bei Polycythaemia vera zum Nachweis von Erythropoetinabhängigkeit.

In eight patients suffering from polycythaemia vera, the proliferation of erythroid colonies in methylcellulose with and without exogenous erythropoietin was studied. After three and five weeks, respectively, no colonies grew. Due to addition of erythropoietin more erythroid colonies proliferated which could be cultivated over nine weeks. The experiments suggest that the erythropoiesis in polycythaemia vera depends on erythropoietin.

Large-scale isolation of middle and higher molecular weight uremic toxins.

Reverse osmosis (40 bar) using membranes with a nominal cut-off of 500 Dalton is a useful method for the desalting and concentration of hemofiltrates (20-30 L) or even dialysates (120-240 L) from patients with end-stage renal failure. The removal of electrolytes and lower molecular weight solutes from the middle and higher molecular weight fractions can be carried out in one step. The freeze-dried residues show characteristic differences in their molecular weight distributions which are dependent upon their origin (Cuprophane dialysates or RP-6-hemofiltrates). Subfractionation is performed using Sephadex G-15 macrocolumns (2 m x 5 cm), the LKB-Ultrogel AcA 54 and Sephacryl S-200 as well as ion exchange chromatography. The fractions are characterized by their ability to suppress the incorporation of 3H-thymidine into rat bone-marrow as well as HeLa cell cultures. The greatest inhibitory activity originates from those fractions which are not dialysable using Visking tubes in vitro. The results indicate that the middle and higher molecular weight spectra do in fact overlap, suggesting that also higher molecular weight substances are involved in uremic intoxication.

[On the existence of a myeloproliferative factor in patients with a myeloproliferative syndrome (author's transl)]. / Zur Frage der Existenz eines myeloproliferativen Faktors bei Patienten mit myeloproliferativem Syndrom.

Serum of patients suffering from a chronic myeloproliferative disorder (polycythaemia, era, osteomyelofibrosis, chronic myeloid leukaemia) and serum of lethally irradiated rats injected before application of a single doses of erythropoietin did not enhance the effect of erythropoietin -- measured with the iron incorporation rate of polycythemic mice. The rationale for these experiments is to try to find a "myeloproliferative factor", which augments the number of stem cells as described in sera of patients with polycythaemia vera, osteomyelofibrosis, and lethally irradiated mice.