Increasing intensity of therapies assigned at diagnosis does not improve survival of adults with acute myeloid leukemia.

We randomized 3375 adults with newly diagnosed acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome to test whether increasingly intensive chemotherapies assigned at study-entry and analyzed on an intent-to-treat basis improved outcomes. In total, 1529 subjects <60 years were randomized to receive: (1) a first course of induction therapy with high-dose cytarabine and mitoxantrone (HAM) or with standard-dose cytarabine, daunorubicin and 6-thioguanine (TAD) followed by a second course of HAM; (2) granulocyte-colony stimulating factor (G-CSF) or no G-CSF before induction and consolidation courses; and (3) high-dose therapy and an autotransplant or maintenance chemotherapy. In total, 1846 subjects ⩾60 years were randomized to receive: (1) a first induction course of HAM or TAD and second induction course of HAM (if they had bone marrow blasts ⩾5% after the first course); and (2) G-CSF or no G-CSF as above. Median follow-up was 7.4 years (range, 1 day to 14.7 years). Five-year event-free survivals (EFSs) for subjects receiving a first induction course of HAM vs TAD were 17% (95% confidence interval, 15, 18%) vs 16% (95% confidence interval 14, 18%; P=0.719). Five-year EFSs for subjects randomized to receive or not receive G-CSF were 19% (95% confidence interval 16, 21%) vs 16% (95% confidence interval 14, 19%; P=0.266). Five-year relapse-free survivals (RFSs) for subjects <60 years receiving an autotransplant vs maintenance therapy were 43% (95% confidence interval 40, 47%) vs 40 (95% confidence interval 35, 44%; P=0.535). Many subjects never achieved pre-specified landmarks and consequently did not receive their assigned therapies. These data indicate the limited impact of more intensive therapies on outcomes of adults with AML. Moreover, none of the more intensive therapies we tested improved 5-year EFS, RFS or any other outcomes.

Prospective randomized trial to evaluate two delayed granulocyte colony stimulating factor administration schedules after high-dose cytarabine therapy in adult patients with acute lymphoblastic leukemia.

In acute lymphoblastic leukemia (ALL), treatment with granulocyte colony stimulating factor (G-CSF) during remission induction shortens granulocytopenia and may decrease morbidity due to infections. However, the optimal timing of G-CSF administration after chemotherapy is not known. In a prospective randomized multi-center study, adult ALL patients were treated with high-dose ARA-C [HDAC, 3 g/m(2) bid (1 g/m(2) bid for T-ALL) days 1-4] and mitoxantrone (MI 10 mg/m(2) days 3-5). They were randomized to receive recombinant human G-CSF (Lenograstim) 263 micro g/day SC starting either from day 12 (Group 1) or day 17 (Group 2). Fifty-five patients (41 male, 14 female) with a median age of 34 years (range: 18-55 years) were enrolled into the study; 50 patients were evaluable. The median duration of neutropenia <500/ micro l after HDAC/MI was 12 days (range: 7-22 days) in the early G-CSF Group 1 and also 12 days (range: 4-22 days) in the late G-CSF Group 2; this was shorter than in the historical control group (15 days, range: 4-43 days, n=46) where the patients received identical cytotoxic treatment without G-CSF. Seventeen infections were observed in 14 patients in Group 1 (47%) and 13 infections in 10 patients in Group 2 (50%) compared to 27 infections in 49 patients of the historical control (54%). In Group 1, the patients received a median of 11 injections with G-CSF (range: 7-22) compared to 7 injections (range: 4-19) in Group 2. The total administered dose of G-CSF in Group 2 was significantly reduced by 40% ( P<0.0001). The delayed start of G-CSF after HDAC/MI in ALL achieves the same clinical benefit compared to the earlier initiation of G-CSF. The reduction of treatment costs by reducing the total G-CSF dose may be important in future treatment with this hematopoietic growth factor.

Remission induction therapy: the more intensive the better?

Intensive induction therapy in acute myeloid leukemia (AML) as in some other systemic malignancies is a strategy fundamentally different from post-remission strategies. Approaches such as consolidation treatment, prolonged maintenance, and autologous or allogeneic transplantation in first remission are directed against the minimal residual disease in which a malignant cell population has survived induction treatment and shows resistance due to special genetic or kinetic features. In contrast, induction therapy deals with naive tumor cells possibly different from their counterparts in remission in terms of their kinetic status and sensitivity. Therefore, in AML the introduction of intensification strategies into the induction phase of treatment has been suggested as a new step in addition to intensification in the postremission phase. As expected from the dose effects observed in post-remission treatment with high-dose cytarabine (AraC) or longer treatment, similar dose effects have been found in induction treatment both from the incorporation of high-dose AraC and from the double-induction strategy used in patients up to 60 years of age. As a particular effect, patients with poor-risk AML according to an unfavorable karyotype, high LDH in serum, or a delayed response show longer survival following double induction containing high-dose AraC as compared to standard-dose AraC. A corresponding dose effect in the induction treatment of patients aged 60 years and older has been found with daunorubicin 60 vs 30 mg/m2 as part of the thioguanine/ AraC/daunorubicin (TAD) regimen with the higher dosage significantly increasing the response rate and survival in these older patients who represent a poor-risk group as a whole. Thus we have been able to demonstrate both in younger and older patients that a poor prognosis can be improved by a more intensive induction therapy. High-dose AraC in induction, however, exhibits cumulative toxicity in that repeated courses containing high-dose AraC in the post-remission period lead to long-lasting aplasias of about 6 weeks. Thus after intensive induction treatment, high-dose chemotherapy in remission may be practicable using stem-cell rescue and may contribute to a further improvement in the outcome in poor-risk as well as average-risk patients with AML. These approaches are currently under investigation by the German AML Cooperative Group (AMLCG). "The more intensive the better" is certainly not the way to go in the management of AML and other systemic malignancies but some increase in intensity may be possible and better.

Acute myeloid leukemia in adults: is postconsolidation maintenance therapy necessary?

Maintenance treatment for patients with acute myeloid leukemia (AML) in remission has recently been controversially discussed and even abandoned by several groups. An analysis of 14 recently published multicenter trials, however, revealed the highest probabilities of relapse-free survival (RFS), in the range of 35% to 42% at 4 to 5 years, only in patients assigned to maintenance treatment as far as adult age and intent-to-treat conditions were considered. After having demonstrated a superior RFS rate from 3 years of maintenance after standard-dose consolidation compared with that from consolidation alone (P = .00004), the German AMLCG requestioned the effect of maintenance randomly compared with sequential high-dose cytosine arabinoside (Ara-C) and mitoxantrone in patients who received intensified induction treatment. The results show an advantage for maintenance treatment (RFS rate of 32%) versus the sequential Ara-C and mitoxantrone treatment (RFS rate of 25%) (P = .021). We conclude that maintenance treatment continues to substantially contribute to the management of adult patients with AML, even as part of recent strategies using intensified induction treatment, and thus appears necessary in these settings.

Differential inhibition of thrombin activity and thrombin generation by a synthetic direct thrombin inhibitor (napsagatran, Ro 46-6240) and unfractionated heparin in patients with deep vein thrombosis. ADVENT Investigators.

BACKGROUND: Direct thrombin inhibitors belong to a new class of antithrombotic drugs whose effects on blood coagulation in vivo in patients suffering from acute thrombotic conditions have not yet been fully explored. METHODS AND RESULTS: One hundred and five patients with acute proximal deep-vein thrombosis were randomized to receive a continuous intravenous infusion of napsagatran, a novel synthetic thrombin inhibitor, at a fixed dose of 5 mg/h (n = 36) or 9 mg/h (n = 25) for five days, or APTT-adjusted unfractionated heparin (UFH, n = 44) for the same time. In these patients, thrombin activity and thrombin generation could be assessed by measuring thrombin-antithrombin III complexes (TAT) and prothrombin fragment 1+2 (F1+2), respectively, on three occasions. At baseline, TAT and F1+2 did not differ among the three groups. On Day 2 (steady state), TAT significantly decreased in all groups, and the decrease was significantly more pronounced in the patients given higher-dose napsagatran. F1+2 decreased significantly only in UFH-treated patients. Two hours after cessation of the infusion, the TAT levels increased in the two napsagatran groups but not in the UFH group, whilst F1+2 went back to the baseline levels in the napsagatran-treated patients but remained low in the UFH-treated patients. There was no rebound effect. CONCLUSIONS: The data presented suggest that direct thrombin inhibition with napsagatran at 9 mg/h is more potent than UFH in attenuating thrombin activity, but is less potent than UFH in inhibiting thrombin generation. The real significance of these findings will have to be substantiated in further trials with clinically relevant endpoints.

An exploratory trial of two dosages of a novel synthetic thrombin inhibitor (napsagatran, Ro 46-6240) compared with unfractionated heparin for treatment of proximal deep-vein thrombosis -- results of the European multicenter ADVENT trial.

One hundred and ten patients with acute proximal deep-vein thrombosis were randomized in a sequential dose-finding design, to receive continuous intravenous infusion of napsagatran, a novel synthetic thrombin-inhibitor, at a fixed dose of 5 mg/h (n = 37) or 9 mg/h (n = 26), or APTT-adjusted unfractionated heparin (n = 47). Oral anticoagulants were started on the 2nd day and the study drug was discontinued from the 5th treatment day, as soon as the International Normalized Ratio was above 2. Control venogram (97 venogram pairs evaluable) after 5-8 days of treatment showed improvement in 3 napsagatran-treated patients (versus none in heparin-treated patients) and worsening in 4 napsagatran-treated patients (versus 2 in heparin-treated patients). The venographic Marder's score did not change among the treatment groups. New lung scan perfusion defects (99 scintigram pairs evaluable) occurred in 4 (11%), 4 (21%), and 4 (10%) patients in the napsagatran (5 mg/h) group, in the napsagatran (9 mg/h) group, and in the heparin control group, respectively. There was no statistically significant difference in any of these endpoints between the 3 groups. No major bleeding was observed and the rare minor bleedings occurred at a similar rate in the three treatment groups. In conclusion, the ADVENT trial has shown data that suggest comparable efficacy and safety of a synthetic, direct thrombin inhibitor (napsagatran) and conventional heparin therapy for treatment of proximal DVT. These results suggest that synthetic direct thrombin inhibitors are a promising class of antithrombotic agents which deserves further development in this field.

[Gastrointestinal lymphomas: results of multimodal therapy in 57 patients of one center]. / Gastrointestinale Lymphome: Ergebnisse einer multimodalen Therapie bei 57 Patienten eines Zentrums.

From 1982-1995, 57 patients with primary gastrointestinal lymphoma were treated with a multimodality therapy. Of these patients, 36 were primary operated, 43 were given an isolated or postoperative chemotherapy and 17 were treated with radiation. Primary operated patients have a significantly better chance of relapse-free survival than those only treated conservatively.

[Prevention of thromboembolism in surgery--results of a survey in West German hospitals]. / Thromboembolie-Prophylaxe in der Chirurgie--Ergebnis einer Umfrage an westdeutschen Krankenhäusern.

UNLABELLED: In 1990 a questionnaire on methods for prevention of deep venous thrombosis (DVT) and pulmonary embolism (LE) was mailed to 940 surgical centers in West Germany (FRG). The return rate was 60% or 564 answers, covering about 1,200,000 operations/year. The results are as follows: (1) Physical therapeutic measures (early mobilisation, elastic stockings) and drug administration are routinely used in all centers. The duration of prophylaxis is 3-8 days in 36% of centers, up to mobilisation in 31%, 9-16 days after operation in 17% and until demission in 16%. (2) A single drug regime is employed in 60% of centers (49% standard heparin, 9% low molecular heparin in combination with DHE) 40% of centers use all three drugs without clear cut guidelines concerning the indications. (3) The reported rates of thromboembolic complications diagnosed by clinical criteria are 0.55 +/- 0.62% for DVT and 0.22 +/- 0.29% for fatal or nonfatal LE. There is no evidence from the analysed data that the drug regimes influences the clinical outcome. CONCLUSION: The need for administration of drugs prevent DVT is widely accepted. A polypragmatic approach seems to be effective. However, standardized regimes for defined clinical conditions are desirable.

[Differential diagnosis of rhonchopathy using the MESAM system]. / Differentialdiagnose der Rhonchopathie mit Hilfe des MESAM-Systems.

A programme for the differential diagnosis of rhonchopathy is reported, based upon the MESAM system developed at the University of Marburg. With this biparametric long-term monitor the snoring noise and the heart beat frequency (a beat-by-beat analysis) were recorded in 94 patients with a history of snoring. Other investigations included tape recordings of the snoring noise, nasoendoscopy, pulsed cineradiography of the pharynx and the recording of the character of the snoring. This programme is much cheaper than a sleep laboratory, but it can distinguish between obstructive sleep apnoea syndrome, habitual rhonchopathy and non-snorers, mainly by means of the characteristic patterns of MESAM recordings. A sleep apnoea syndrome was diagnosed in 19 patients and habitual rhonchopathy in 38 patients, whereas 33 patients were regarded as non-snorers. Ten of our 19 patients with sleep apnoea were re-examined by a sleep laboratory and the diagnosis was proved in all of these cases. In the 38 patients with habitual rhonchopathy auditory analysis of the snoring noise classified 23 patients as velar and 10 as pharyngeal snorers; 5 patients showed a mixed type of rhonchopathy. The questionnaire accompanying the MESAM system, nasal endoscopy and cine films support the individual diagnosis by revealing typical complaints and characteristic organic findings and thus contribute to the differential diagnostic screening. However, the three groups do overlap quite markedly with respect to symptoms und organic findings. In summary, the MESAM system provides an economically viable examination programme that can be used routinely by the otorhinolaryngologist for the differential diagnosis of rhonchopathy.

[The clinical course of coumarin-induced necrosis]. / Klinischer Verlauf bei Cumarin-Nekrose.

In three patients painful reddening of a well-circumscribed area of the skin occurred within five days of starting anticoagulant treatment with phenprocoumon (Marcumar), and within a short time it developed into a full-blown picture of coumarin necrosis. The indication for phenprocoumon was, in the first patient (a 29-year-old mother lying-in after her second child had been born) an increased platelet count and the presence of high risk factors for thromboembolism. In the second patient (25-year-old man) and the third one (45-year-old woman) it was secondary prophylaxis after pulmonary embolus and deep-vein thrombosis, respectively. All three patients were very obese and had a drug allergy, as well as other allergies (bronchial asthma in Cases 1 and 2; allergic rhinitis in Case 3). Phenprocoumon was at once discontinued in all three patients and low-dose heparin administration (Cases 1 and 3) or dextran infusion (Case 2: heparin intolerance) started. All three needed excision of the necrotic tissue with grafting to the skin defect. The coexistence of obesity and allergic diathesis may thus present an especially high risk for coumarin necrosis.

Treatment of advanced renal cell cancer with recombinant interferon alpha as a single agent and in combination with medroxyprogesterone acetate. A randomized multicenter trial.

The response rates in metastatic renal cell cancer (RCC) after chemotherapy, hormonal treatment, or immunotherapy rarely exceed 15%. Recently, interferon alpha (IFN alpha) was used for treatment of this disease in several studies which also demonstrated response rates of 15%. In order to test whether IFN therapy combined with hormones would result in higher response rates we compared single agent IFN therapy with a combined therapy of rIFN alpha 2C plus medroxyprogesterone acetate (MPA) in a randomized multicenter trial. The rIFN alpha 2C (2MU) was given s.c. 5 times per week for 8-12 weeks and subsequently once weekly until week 48. In the combined treatment, 750 mg MPA was given p.o. daily until week 48 in addition to the IFN as described. The overall response rate in 93 evaluable patients was 5.4% corresponding to 2 complete and 3 partial responses. Median survival was 7 months in both treatment groups. These data confirm the ineffectivity of low IFN doses for treatment of RCC. The low response rate is not increased by addition of MPA to IFN. The analysis of other IFN studies suggests that not only IFN doses but also IFN sources may influence response rates in metastatic RCC.

[Bell's palsy as the initial symptom of HIV infection]. / "Bellsche Parese" als Erstsymptom einer HIV-Infektion.

60% of all HIV-infected patients develop neurological deficits during the course of their disease. The facial paralysis of a 47 year old man which presented as a Bell's palsy is nevertheless an unusual first symptom of HIV infection.

[Cutaneous paresthesia in high-dose intravenous dexamethasone therapy in oncology]. / Missempfindungen der Haut bei hochdosierter intravenöser Dexamethason-Behandlung in der Onkologie.

Seventeen oncological patients reported unpleasant but clinically harmless skin sensations directly after intravenous injection of dexamethasone, persisting for 2-4 minutes. In 16 cases, these paraesthesias (tingling, burning, itching, twinging) occurred in the genital or perineal area. In one case, the symptoms started in this area and then extended over the entire truncus integument for a short period. The cause of this obviously drug-induced side effect is unknown.

Response of total and 'free' thyroid hormones and diiodotyrosine to bovine TSH in subclinical hypothyroidism.

Thirty-three patients with Addison's disease were studied. Twenty-two had idiopathic Addison's disease; within this group, 14 patients had clinical or subclinical hypothyroidism, and 16 had increased titres of thyroid autoantibodies. Five patients had tuberculous, and eight had unclassifiable Addison's disease; only one patient in the latter group had evidence of thyroid autoimmunity. A stimulation test with 15 mU bTSH/kg was performed in three patients with Schmidt's syndrome (coexisting Addison's disease and manifest primary hypothyroidism), 15 patients with either subclinical hypothyroidism or increased titres of thyroid autoantibodies, 10 patients without thyroid involvement, and 10 normal controls. There was no detectable increase of 'free' and total thyroid hormones in Schmidt's syndrome. The mean increases after 3-4 h of T4, fT4, T3 and fT3 were 22, 35, 63 and 66%, respectively, in patients without thyroid involvement, and 13, 24, 46 and 45% in patients with subclinical hypothyroidism. 'Free' but not total thyroid hormones rose significantly (P less than 0.01) higher in patients without signs of thyroid involvement than in patients with subclinical hypothyroidism and/or thyroid autoantibodies. Thyroid hormone response to bTSH in Addison's disease with apparently healthy thyroid glands was not different from normal controls. Serum diiodotyrosine rose in all groups except in hypothyroidism; hypothyroid patients had, however, basal levels well within the normal range. Thus, thyroid hormone synthesis appears to be blocked at a point distal to diiodotyrosine formation in this particular situation. These results support the assumption that TSH elevation in idiopathic Addison's disease is due to coexisting thyroid autoimmunity and that it reflects incipient thyroid failure.(ABSTRACT TRUNCATED AT 250 WORDS)

HTLV III antibodies and immunological alterations in hemophilia patients.

The clinical, immunological, and serological status of 28 patients with hemophilia A and of 13 patients with hemophilia B was investigated. Thirty-four patients were treated regularly by clotting factor concentrates and 7 patients had been substituted only 1 to 4 times. Almost all patients with severe hemophilia suffered from hepatopathy. No patient had clinical evidence of the acquired immunodeficiency syndrome (AIDS). Asymptomatic hemophiliacs showed a decreased number of T-helper (OKT 4) cells and an increased number of T-suppressor (OKT 8) cells, which resulted in an inversed OKT 4/OKT 8 cell ratio. Natural killer cell activity of all patients was decreased compared to controls. After culture there was no significant difference of NK cell activity between hemophiliacs and controls. This phenomena was interpreted as a possible maturation defect of NK-cells in vivo. No relationship between immunological alterations and hepatopathy, hepatitis markers, CMV antibodies, amount and source of required factor concentrates, and the kind of hemophilia was observed. IgG immunoglobulins were higher and the OKT 4/OKT 8 ratio lower in the eight patients with lymphadenopathy than in patients without lymphadenopathy. The prevalence of antibodies to human T-lymphotropic virus (HTLVIII) was measured in 35 hemophiliacs and in 25 polytransfused patients, most of whom were suffering from acute leukemia. In 8 of 35 hemophiliacs antibodies to HTLVIII virus were detected by an enzyme linked immunosorbent assay (ELISA) and confirmatory tests. All seropositive patients were treated by blood products from the United States. Eight hemophiliacs treated by factor concentrates from German donors only were seronegative. In comparison 2 of 25 examined non-hemophilia patients receiving multiple blood products from local donors were seropositive for HTLVIII. The results show that hemophilia patients treated by imported clotting factor concentrates have a high risk of HTLVIII positivity. Hemophiliacs substituted by blood products obtained by local donor pools have only a small risk of infection. Because non-hemophiliac polytransfused patients had HTLVIII antibodies, there must be asymptomatic virus carriers in the local donor pool. The HTLVIII antibody screening of all donors and the heat treating of factor concentrates will give better therapeutic safety.