[Quality of life in patients with remitting-relapsing multiple sclerosis in Germany]. / Lebensqualität bei Patienten mit schubförmiger MS in Deutschland.

The concept of health-related quality of life (QoL) includes physical, psychological,and social aspects. This pertains to consequences of chronic diseases and their therapies beyond biological or pharmacological relations. A considerable amount of literature concerning QoL has been published with regard to neurological and non-neurological entities. This study summarizes data from a study in 717 persons with remitting-relapsing multiple sclerosis (MS). Of them,576 could be reevaluated longitudinally after 1 year of treatment with interferon-beta 1a (44 microg subcutaneous Rebif once weekly). Compared to populations of healthy controls or other patients, considerable reductions in the eight subscales and both physical and emotional sum scales of the German version of the short form of the Rand Health Questionnaire (SF-36) questionnaire were assessed. These reductions were even more pronounced in persons with gait impairments. Most SF-36 scales only modestly correlated to physical disability. This indicates that QoL as reported by patients does not depend solely on the physical symptoms of MS. Most findings remained stable for the study population as a whole during 1 year of therapy, while statistically significant improvements were found in clinical responders as defined in this study (relapse-free, physically stable, stable or improved in physician's judgement). Side effects of therapy were not reflected in lower QoL scale values. Implications of findings for future concepts in MS therapy are discussed.

Mx proteins in blood leukocytes for monitoring interferon beta-1b therapy in patients with MS.

OBJECTIVE: To correlate Mx protein (Mx) levels in lysed blood leukocytes with the clinical response to interferon (IFN) beta-1b (IFNbeta-1b) in relapsing-remitting MS (RR-MS) patients for monitoring treatment. BACKGROUND: Intracellular Mx expression is exclusively induced by the type I IFNs (IFN-alpha, -beta, and -omega) or by viruses and is strongly increased under IFN treatment. Quantitative determination of Mx allows objective assessment of biological effects of IFN. METHODS: Mx protein levels were measured in blood leukocyte lysates from IFNbeta-1b-treated RR-MS patients by ELISA and correlated to clinical parameters, including relapse rate and clinical deterioration. RESULTS: In stable IFNbeta-1b-treated MS patients, Mx levels were significantly increased compared to patients with or without immunosuppressive treatment. In IFN-1b-treated MS patients during relapse, Mx levels were significantly lower than during stable phases of the disease. Mean values of Mx (MVMx) over time of treatment in patients with a reduction of relapse rate were significantly higher than in patients without response. CONCLUSION: Mx levels in lysed blood cells may represent a useful surrogate marker for IFNbeta-1b activity corresponding to the clinical response during treatment of MS.

Expression of interferon-inducible Mx-proteins in patients with IgA nephropathy or Henoch-Schönlein purpura.

Both viral infections and dysregulated cytokine synthesis have been implicated in the pathogenesis of immunoglobulin A nephropathy (IgAN) and Henoch-Schönlein purpura (HSP). Mx proteins are specifically induced by type I interferons (IFN-alpha, -beta, -omega) and are very sensitive in detecting, for example, virus-induced, in vivo production of IFN-alpha/-beta, because the biological half-life of Mx (approximately 3 days) markedly exceeds that of IFN-alpha/-beta (20 to 90 minutes). Mx concentrations in leukocytes were measured by enzyme-linked immunosorbent assay (ELISA) in 79 blood samples of 35 patients with IgAN and five with HSP. No patient showed symptoms of infections at the time of the examination. Compared with normal leukocyte Mx concentrations (<2 mU/1,000 leukocytes), only 3 of 79 samples of IgAN/HSP patients showed mildly elevated Mx concentrations (range, 2.2 to 3 mU/1,000 leukocytes). By contrast, patients with increased endogenous IFN production (lupus erythematosus) or patients treated with IFN-alpha2 showed leukocyte Mx concentrations of up to 35 mU/1,000 leukocytes. In patients with IgAN and HSP, leukocyte Mx concentrations were not correlated with various clinical parameters. Immunohistochemically, no renal Mx expression could be detected in eight renal biopsy specimens of patients with various stages of IgAN, whereas control specimens (skin of patients treated with IFN-alpha2) showed abundant cellular Mx expression. Furthermore, human mesangial cells in vitro showed marked Mx production after exposure to IFN-alpha or IFN-beta. We conclude that, in patients with IgAN/HSP, no evidence of an activation or dysregulation of the type I interferon system can be detected.

Treatment of extrahepatic biliary atresia with interferon-alpha in a murine infectious model.

The etiology of extrahepatic biliary atresia (EHBA) in newborns remains unknown, although a first infectious animal model with complete obstruction of the common bile duct could be established. Intraperitoneal inoculation of newborn Balb/c mice with rhesus rotavirus induced cholestasis, leading, in most cases, to biliary atresia with lethal outcome, similar to EHBA in human newborns. The influence of interferon-alpha (IFN-alpha) on the hepatotropism of rotavirus infection was investigated in this animal model. Single-dose therapy with 10000 IU of IFN-alpha protected all rhesus rotavirus-infected pups from cholestatic disease. The same dose, injected 5 d after infection, had no protective effect. Starting with onset of cholestatic symptoms, the treatment with 10000 IU of IFN-alpha daily showed good results in 29 mice. Seventy-six percent of the mice recovered after 1 wk of therapy. Histologic investigation revealed normal findings in the hepatobiliary tract of clinically normal mice. Twenty-one percent of the descendants of infected and prophylactic IFN-alpha-treated mice showed cholestatic symptoms after infection with rhesus rotavirus (79% in an untreated control group) and a milder form of the illness. In conclusion, we found that prophylactic treatment with IFN-alpha prevented the hepatobiliary system of newborn Balb/c mice from severe damage by rhesus rotavirus in this artificially designed infectious model for EHBA. Infected and icteric mice, treated for 1 wk with IFN-alpha, had good prospects for recovery and prevention of complete and irreversible occlusion of the extrahepatic bile ducts. Infected and prophylactic IFN-alpha-treated dams gave good protection to their descendants. This means that EHBA in this model could probably be averted by maternal antibodies against rotavirus.

Adjuvant immunotherapy in malignant melanoma: impact of antibody formation against interferon-alpha on immunoparameters in vivo.

In an adjuvant clinical trial for high-risk patients with malignant melanoma by using recombinant interleukin-2 (rIL-2) and recombinant interferon-alpha 2b (rIFN-alpha 2b), we monitored the development of antibodies against rIFN-alpha and various immunoparameters as biologic markers for IFN activity in vivo. Thirty-one patients (22 men, nine women) with high-risk malignant melanoma received eight 6-week cycles of rIL-2 and rIFN-alpha. Serum samples of all patients were screened for the presence of antibodies against IFN-alpha by a solid enzyme immunoassay (EIA). Specimens testing positive in the EIA were assessed for their ability to neutralize the antiviral effects of IFN-alpha in vitro in an antibody-neutralizing bioassay (ANB). Furthermore, serum levels of neopterin, beta 2-microglobulin, soluble IL-2 receptor (sIL-2R), anticardiolipin and antithyroglobulin were evaluated. Of 31 patients, 11 (36%) developed binding antibodies; three (27%) of them had antibodies with neutralizing capacities (range, 350-28,000 INU/ml). Of male patients, 8 (36%) of 22 versus 1 (11%) of nine female patients developed antibodies. Statistical analysis (unpaired t test) revealed that all patients with antibody titers showed significant (p < 0.04) lower serum levels of beta 2-microglobulin and reproducible decreases in sIL-2R levels, whereby those with neutralizing antibodies showed significantly (p < 0.0001) lower values than did those with binding antibodies. Elevations of anticardiolipin (17 of 31) and antithyroglobulin (one of 31) were not correlated to the presence of IFN antibodies. Our results show the in vivo significance of antibodies against rIFN-alpha, especially of those with neutralizing capacities. Monitoring of antibody formation as well as immunoparameters like beta 2-microglobulin in clinical trials can contribute to identifying patients who, if necessary, might benefit from alternative IFN treatment, for instance, by using natural IFNs.

Intracellular staining of Mx proteins in cells from peripheral blood, bone marrow and skin.

AIM/BACKGROUND: The Mx proteins are known to be specifically and dose dependently induced in mononuclear cells (MNC) by type I interferons (IFN). The aim of this study was to establish a staining method for the human intracellular Mx proteins, MxA and MxB, in leucocytes and bone marrow and skin cells. METHODS: Several monoclonal antibodies directed against the MxA and MxB proteins were generated. These antibodies were used to stain Mx proteins in both frozen and paraffin wax sections using the standard alkaline phosphatase anti-alkaline phosphatase (APAAP) method. RESULTS: Granulocytes, monocytes and lymphocytes extracted from freshly collected blood from 21 healthy subjects did not stain. After incubating MNC from these subjects with IFN alpha 2b for 48 hours, Mx proteins were detected in monocytes and lymphocytes. Within two days of starting treatment with subcutaneous IFN alpha 2b, granulocytes, monocytes and lymphocytes of 16 patients with cancer stained strongly for Mx proteins. The intensity of staining was correlated with the Mx content of whole blood measured using a specific ELISA. Prior to IFN treatment, cells from bone marrow and skin tissue specimens were negative for Mx proteins with the exception of endothelial cells. During treatment with IFN alpha 2b, nearly all cells from bone marrow and skin stained intensely. CONCLUSIONS: These new monoclonal antibodies facilitate the detection of Mx positive cells in peripheral blood and in frozen or paraffin wax specimens. The advantage of this staining method is that individual cells which have responded to viruses or biologically active IFN alpha, beta or omega can be identified.

Epitopes recognized by neutralizing therapy-induced human anti-interferon-alpha antibodies are localized within the N-terminal functional domain of recombinant interferon-alpha 2.

During prolonged recombinant interferon (rIFN)-alpha 2 therapy, a minority of patients develop high-titer neutralizing IFN-alpha antibodies. Sera from nine IFN-alpha antibody-positive patients were studied to characterize the specificity of anti-IFN-alpha neutralizing antibodies by their ability to inhibit the antiviral and antiproliferative activity of different rIFN-alpha subtypes and rIFN-alpha 1/alpha 2 hybrids. These therapy-induced antibodies (Tab) were compared with IFN-alpha-specific autoantibodies (Aab) from two patients with systemic lupus erythematosus who had never received any exogenous IFN-alpha. Although IFN-alpha subtypes are closely related in structure, Tab inhibited the antiviral activity of only recombinant (r)IFN-alpha 2 and rIFN-alpha 6, but not or slightly that of rIFN-alpha 1, -alpha 7, -alpha 8 and -alpha 14. Furthermore, of four different rIFN-alpha 1/alpha 2 hybrids tested, Tab inhibited only those which contained the N-terminal residues 17-64 of rIFN-alpha 2. Comparison of the primary sequences of neutralized and not neutralized subtypes suggests an epitope involving the residues 22-31 of IFN-alpha 2 is recognized. Thus, Tab block rIFN-alpha 2 by reacting with only one of two functional domains. In contrast, Aab possessed a broad specificity and neutralized both the antiviral and antiproliferative activity of rIFN-alpha 2, -alpha 6, -alpha 7, -alpha 8, and -alpha 14. They also neutralized all four rIFN-alpha 1/alpha 2 hybrids tested. These data demonstrate that Tab are highly specific for the therapeutic IFN-alpha subtype and specifically neutralize rIFN-alpha 2 by binding to its N-terminal functional domain.

[Therapy of chronic myeloid leukemia with interferon-alpha. A decade of experiences]. / Therapie der chronischen myeloischen Leukämie mit Interferon alpha. Erfahrungen aus einem Jahrzehnt.

PATIENTS AND RESULTS: One hundred and fifty-nine patients with chronic myelogenous leukemia have been treated in six studies during 10 years at Hannover Medical School University Center. The prognosis of 111 patients without pretreatment has been improved compared to conventional therapy with a median survival of 5.7 years. Cytogenetic remissions have been induced in all studies followed for a longer time. The most pronounced improvement of prognosis has been observed in these patients. CONCLUSIONS: Several conclusions can be drawn on the basis of the results on the different treatment concepts: 1. Patients with pretreatment have an unfavourable response to interferon. 2. There is a likely effect of the dose of Interferon alpha on the frequency of cytogenetic remissions. 3. The combination of Interferon alpha and interferon gamma has been toxic and ineffective in a pilot study. 4. The combination of interferon and cytosine arabinoside has a positive impact on the frequency of cytogenetic remissions. A continuous parallel application of both drugs seems to be most effective in this respect. An ongoing trial has been initiated to compare a fixed combination of Interferon alpha and cytosine arabinoside and with hydroxyurea respectively. Additionally the feasibility of autologous peripheral blood stem cell transplantation will be studied in patients with insufficient response to the interferon treatment.

Factors inhibiting IFN activity.

Several factors may inhibit the activity of IFNs. Some of these occur naturally, others are therapy-induced or artificial. Naturally occurring antibodies appear to have a much broader reactivity than therapy-induced antibodies. Naturally induced antibodies are reported in patients suffering from chronic graft-versus-host disease after bone marrow transplantation. Differences in the reported immunogenicity between interferons may not be due to the minor variation in amino acid sequence. The clinical significance of therapy-induced antibodies has been unclear. In patients treated for chronic hepatitis C, antibody formation is closely related to relapse. In animal studies the efficacy of treatments targeting the IFN receptor interaction has been shown. Soluble IFN-gamma receptor inhibits the development of autoimmune diseases in mice. Monoclonal antibodies to the IFN-alpha receptor protects against allograft rejections in monkeys. Two naturally occurring inhibitors of IFN action were reported. The clinical significance and structure of these inhibitors remain elusive.

Common variable immunodeficiency (CVID) and MxA-protein expression in blood leucocytes.

The underlying immunopathogenic mechanism of CVID has been suspected to involve a chronic viral infection or an autoimmune condition. However, formal proof of viral infection is lacking. Measurement of MxA-protein in leucocyte lysates is a sensitive test for evaluating the activation of the host's interferon system. Both viral infections and autoimmune diseases such as systemic lupus erythematosus (SLE) strongly induce MxA-protein in peripheral leucocytes. We therefore examined 15 patients with longlasting hypogammaglobulinaemia for MxA-protein induction in vivo: 13 patients suffered from CVID, one from hyper-IgM syndrome, and one patient had chronic B lymphocytic leukaemia associated with immunoglobulin deficiency and chronic papilloma virus infection (condylomata accuminata). Only the latter patient exhibited a strong MxA-protein expression; two CVID patients were borderline positive, and the remaining 12 patients including the hyper-IgM syndrome were MxA-protein-negative. There was no relationship between MxA expression and low CD4/CD8 ratios or increased CD8/CD57+ T cell counts, although both conditions are often observed in CVID as well as in chronic viral infections. When exposed in vitro to interferon-alpha (IFN-alpha), peripheral blood leucocytes of four MxA-negative patients were capable of producing normal amounts of MxA-protein. Taken together, these results argue against a viral or autoimmune pathogenesis of CVID.

No synergistic activity of epirubicin and interferon-alpha 2b in the treatment of hepatocellular carcinoma.

Single-agent activity for anthracyclines reflected by response rates of 10%-30% has been reported in patients with advanced hepatocellular carcinoma (HCC). Preclinical data indicate that alpha-interferon could enhance the cytotoxic activity of the anthracycline Adriamycin or its analog epirubicin. In a phase I/II study, 31 patients with biopsy-proven inoperable HCC were treated with interferon-alpha 2b given s.c. at a dose of 3 x 10(6) units/m2 per day for 5 days per week plus weekly epirubicin given at 25 mg/m2 as an i.v. bolus. The protocol called for 4 consecutive weeks of treatment followed by 1 week off treatment. In all, 15 patients had been previously treated; 6 patients had failed hormonal therapy (tamoxifen), 5 patients had failed prior anthracycline treatment, and 4 patients had received chemoembolization of the tumor and had subsequently progressed. A total of 30 patients were evaluable for response. In all, 1 patient (3%) achieved a partial response for 8+ months and 11 patients (35%) achieved stabilization of disease. Six patients had a fall in alphafetoprotein (AFP) values of > 50% during therapy. The median survival for all patients was 9.5 months (range, 3-34+ months). The main side effects were hematological toxicity and fever, both of which were considered tolerable. As an indicator of the immunostimulatory effects of interferon, an elevation in serum markers of inflammation [C-reactive protein (CRP), beta 2-microglobulin] was found in 15%-20% of patients. All patients had measurable Mx protein production during therapy, but these effects were not correlated to the clinical response. The clinical response rate achieved in this trial indicates that the combination of interferon and epirubicin, at least when used on the schedule reported herein, is not superior to treatment with either agent alone for patients with advanced HCC. However, single patients achieved a prolonged progression-free interval (8-10+ months) on this therapy, and it may therefore be an option for patients who have failed prior hormonal or single-agent anthracycline therapy.

Quantitation of interferon-induced Mx protein in whole blood lysates by an immunochemiluminescent assay: elimination of protease activity of cell lysates in toto.

Due to the rapidly expanding usage of interferons and its costliness of therapy, it is important to evaluate the clinical efficacy of the various interferons. Directly assaying circulating interferon is technically quite difficult. Here, we present an alternate method to evaluate interferon therapy by assaying a unique protein, called Mx protein, which is a 78 kDa cytoplasmic protein selectively induced by type-1 interferon in human leukocytes. The current assay is a two-site chemiluminescent immunoassay, designed to detect Mx protein in whole blood lysates. Since the Mx protein once solubilized, is highly susceptible to proteolysis in whole blood lysates, we have devised a new procedure both to maximize its solubility and virtually eliminate its proteolytic degradation. A mouse monoclonal antibody conjugated to the derivatized-paramagnetic particles and an acridinium ester-labeled antibody serve as the solid phase capture and detector antibodies, respectively. This assay is applicable to both manual and automated modes with a detection limit of Mx protein at 20 ng/ml whole blood. Availability of a reliable assay for Mx protein should facilitate the clinical evaluation of many of the newly constructed type-1 interferons.

Strong transient expression of the type I interferon-induced MxA protein in hepatitis A but not in acute hepatitis B and C.

The human MxA protein is a new specific marker for type I interferon activity both in vitro and in vivo. In the study presented here, this interferon-induced marker, as well as the 2',5'-oligoadenylate synthetases, was measured in circulating mononuclear cells from 21 patients with acute hepatitis A, 20 patients with acute hepatitis B and 14 patients with acute hepatitis C for determination of the activation of the interferon system in these viral diseases. In acute hepatitis A a strong expression (10 of 10 patients) of the MxA protein and the 2',5'-oligoadenylate synthetase activity in peripheral-blood mononuclear cells was observed during the first 2 wk after onset of clinical symptoms. In this period the MxA protein concentrations reached levels similar to those measured in patients treated with up to 5 x 10(6) IU interferon-alpha three times a week. Beyond wk 3, in eight of eight patients with hepatitis A no increased MxA protein levels were found. In contrast, peripheral-blood mononuclear cells from patients with acute hepatitis B contained either no measurable MxA protein or only slightly higher levels of the MxA protein, as did those of most patients (12 of 14) with acute hepatitis C. The MxA protein levels of both hepatitis B and C patients were significantly lower (p < 0.05) than those found in hepatitis A patients. Furthermore, sera from 6 of 10 patients with hepatitis A, but none of 10 patients with acute hepatitis B and C, contained measurable MxA protein. This serum MxA protein may originate from interferon-exposed and subsequently damaged liver cells.(ABSTRACT TRUNCATED AT 250 WORDS)

Low dose alpha interferon treatment in chronic hepatitis B virus infection.

Fifty eight patients with chronic viral hepatitis B (HBV) were randomised in a prospectively controlled trial. Thirty patients were treated with 3 million units (MU) of interferon alfa-2b subcutaneously thrice weekly for four months. Twenty eight controls received no treatment. The follow up period after treatment was six months. Twenty eight treated patients and 27 controls completed the protocol. One woman in the treatment group showed a complete response, and eight other treated patients (32%) showed a partial response. Three patients in the control group (11%) lost hepatitis B e antigen and HBV-DNA spontaneously. This finding is statistically significant (p < 0.05). The elimination of HBV markers from the serum was associated with a return to normal of serum aminotransferase activities. Reactivation of hepatitis was not observed after seroconversion.

Non-MHC-restricted T-cell interaction with B cells: role of the T-cell receptor.

Non-specific antibody production usually accompanies the T-cell-regulated B-cell response. In this paper the mechanisms involved in non-MHC-restricted T-B-cell interaction were studied. As previously shown for NK cells, activated B cells induce IFN-gamma and TNF alpha production in non-MHC-restricted cytotoxic T lymphocytes (NrCTL). Using an in vitro model system, we demonstrate that direct cell-cell interactions are required to induce these cytokines in NrCTL. Receptor ligand systems involved are leucocyte function antigen-1/intercellular adhesion molecule-1 (LFA-1/ICAM-1)(CD11a, CD18/CD54), T11/LFA-3 (CD2/CD58), and the clonotypic T-cell receptor (TCR) structure NKTa of JT9/JT10 with its non-MHC-related target antigen TNKtar (4F2). Cytokine production can be induced by activating monoclonal antibodies against CD2R. Antibodies against the clonotypic TCR (NKTa) or CD3 had no cytokine-inducing effect on NrCTL cultured alone, but were able to retrieve the effect of blocking the target antigen on co-cultured B cells. We could further demonstrate that the inhibition of the TCR/target antigen interaction could be overcome by close cell-cell contact culture conditions. From these findings it is concluded that the role of the TCR in non-MHC-restricted cell-cell interaction is to facilitate LFA-1/ICAM-1-mediated effector target adhesion in a specific way rather than to mediate direct activating signals upon lymphokine production or cytotoxicity.

A whole blood immunoassay for the interferon-inducible human Mx protein.

Mx protein, an intracellular protein induced by type I interferons (IFNs), is useful as a marker for the IFN-induced state. It is detectable, for example, in leukocytes of patients undergoing IFN-alpha treatment as well as in patients suffering from viral or autoimmune diseases. For immunizations and standardizations, recombinant human MxA protein was expressed in Escherichia coli and purified from inclusion bodies by several steps of chromatography. Two monoclonal antibodies against nonoverlapping epitopes and specific for human Mx protein were selected to establish a simple two-site immunometric enzyme assay. In addition, a monoclonal antibody also reacting with Mx proteins of other species was identified. Prior to assay, whole blood samples were lysed with a nonionic detergent. The sample was incubated on wells coated with a first monoclonal antibody (1304.5.32) together with a second biotinylated monoclonal (1302.34.16), which, after washing, was revealed by an avidin-alkaline phosphatase system. Limit of detection was 5 ng/ml. In two-thirds of normal blood samples (n = 87), Mx protein levels were below 5 ng/ml; 25 samples (29%) had Mx levels between 5 and 50 ng/ml; and 4 samples (5%) were above 50 ng/ml. No Mx was found in plasma, and the mononuclear cell fraction accounted for the bulk of Mx in blood. In vitro, as determined by flow cytometry, monocytes and lymphocytes accumulated Mx protein for 24 h with similar kinetics and remained at plateau levels for more than 70 h. Monocytes contained around eight times more Mx than lymphocytes. The immunoassay was also suitable for detecting Mx after IFN induction in heparinized blood.

Effective natural interferon-alpha therapy in recombinant interferon-alpha-resistant patients with hairy cell leukemia.

To explore the relationship between anti-interferon-alpha (anti-IFN-alpha) antibodies and loss of clinical responsiveness to IFN-alpha treatment, we examined sera from 59 patients with hairy cell leukemia who responded to therapy with recombinant IFN-alpha-2a (rIFN-alpha-2a). During the first 2 years of therapy, 10 patients developed rIFN-alpha-2a-neutralizing and 15 rIFN-alpha-2a-binding antibodies. Nine of the 59 initially responding patients became resistant to rIFN-alpha-2a and suffered a relapse of the disease at 7 to 24 months of treatment. All nine relapsing patients tested positive for both neutralizing and binding antibodies with titers above 400 INU/mL, while none of the antibody-negative patients relapsed. Six patients with detectable binding antibody titers below 400 INU/mL continued to respond to treatment. By measuring the IFN kinetics and the levels of the IFN-induced Mx-homologous protein in mononuclear cells after a single injection each of rIFN-alpha-2a and nIFN-alpha the IFN antibodies of eight of the nine resistant rIFN-alpha patients were found to be highly specific for rIFN-alpha-2a. Therefore, these eight patients were switched to natural IFN-alpha (nIFN-alpha) therapy at doses of 3 million IU, three times a week. All eight patients responded to treatment with nIFN-alpha, achieving durable objective responses similar to those obtained previously with rIFN-alpha-2a. These data clearly demonstrate that rIFN-alpha antibody-positive patients can effectively be treated with nIFN-alpha.

[Multicenter prospective controlled study of therapy of chronic myeloid leukemia. Comparison of busulfan, hydroxyurea and interferon alpha (April 1990 status)]. / Multizentrische prospektive kontrollierte Studie zur Therapie der chronisch myeloischen Leukämie. Vergleich von Busulfan, Hydroxyurea und Interferon alpha (Stand April 1990).

In a multicenter study it is being determined, whether the use of hydroxyurea or of interferon alpha instead of busulfan prolongs 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 September 5, 1990, 593 CML-patients had been randomized, 221 for busulfan, 228 for hydroxyurea and 144 for interferon alpha. The average age is about 51 years. By April 30, 1990, 106 patients had reached the end of the chronic phase, 126 had died. The median survival of Philadelphia-positive patients was 3.95 years, that of all patients 3.75 years. The median observation time of all patients was 1.34 years (mean 1.60 years). At present, no significant difference in survival is recognizable between the three treatment arms, although fewer adverse effects have been observed in the hydroxyurea arm.