Abstract: Veno‐occlusive disease (VOD) of the liver is a frequent and life‐threatening complication of BMT. Recently, successful treatment by t‐PA has been reported but has been compromised by fatal bleeding events. Therefore, t‐PA application should be restricted to patients with severe VOD. However, moderate and severe forms of VOD are difficult to distinguish in early stages. We analyzed plasma levels of cross‐linked fibrin degradation products (D‐dimer) and soluble endothelial adhesion molecules such as sE‐selectin, sVCAM‐1 and sICAM‐1 in 10 consecutive patients undergoing allogeneic BMT to evaluate their use in identifying severe forms of VOD. During the observation period, 4 episodes of VOD occurred, 2 of which were fatal due to early onset of multiorgan failure. Concentrations of D‐dimer generally increased after transplantation. However, there was an additional significant increase in D‐dimer levels during severe VOD. Thus, D‐dimer levels above 1000 μg/1 were only found in 2 cases with severe VOD and fatal outcome. When compared with bilirubin concentrations substantial increases of D‐dimers appeared earlier during the course of severe VOD. In contrast, VOD episodes were not accompanied by significant increases in sE‐selectin, sVCAM‐1 and sICAM‐1 levels. It is concluded that measurement of D‐dimer concentrations may aid accuracy to the early diagnosis of severe VOD.

The chronic myeloproliferative disorders (MPD), predominantly polycythemia vera and essential thrombocythemia, are characterized by a high incidence of thromboembolic and, to a lesser degree, hemorrhagic complications. The disease process in chronic MPD affects a pluripotent progenitor cell and results in trilineage hematopoietic proliferation. Clonal involvement of megakaryocytopoiesis is regarded as the main origin of thromboembolism in MPD and results in abnormal platelet production. These platelets show increased size heterogeneity and ultrastructural abnormalities, and their function in vitro is in many ways impaired with a high degree of individual variability. Elevated levels of platelet-specific proteins, increased thromboxane generation, and expression of activation-dependent epitopes on the platelet surface are common on chronic MPD, and may reflect an inappropriate state of platelet activation. Although a variety of platelet receptor deficiencies and some defects of intracellular signaling pathways have been identified, the different platelet defects in MPD could not be traced back to an underlying general pathogenetic mechanism. On progression of chronic MPD to more advanced stages of the disease, the number of platelet abnormalities tend to increase. Cytoreductive drugs may partly improve platelet dysfunction, and platelet inhibitory agents reduce symptoms of platelet activation. However, neither of these therapeutic principles is able to normalize platelet function in MPD. As an alternative to conventional treatment, specific suppression of clonal megakaryocyte growth and recovery of polyclonal hematopoiesis may be achieved by biologic agents such as interferon alpha. Such treatment strategies may prevent thromboembolic complications together with hematologic symptoms and progression of the disease and should be further evaluated in prospective studies.

Severe pancytopenia associated with moderate hepatosplenomegaly, increased serum lactic dehydrogenase (LDH) levels, and hypogammaglobulinemia were found in a young male patient. Bone marrow histology showed extensive fibrosis, hypoplasia of erythro- and granulocytopoiesis, and hyperplasia of megakaryocytopoiesis associated with histiocytic fat cell phagocytosis and infiltration of abnormal lymphocytes, compatible with lymphoid myelofibrosis. Striking chromosomal aberrations indicating karyotype evolution were also demonstrated by cytogenetic analyses (47, XY, +3 / 47, XY, +3, 1p+ / 46, XO, +3, 1p+, -Y). The clinical course was characterized by cyclic febrile episodes accompanied by excessive increase of serum LDH levels and leukocyte counts, and decrease of platelet counts, followed by spontaneous regression. Further diagnostic procedures, including two liver biopsies and computed tomography, did not detect any manifestation of lymphoma. Eventually, the patient developed rapidly progressive, lethal pulmonary aspergillosis. At autopsy, high grade B cell lymphoma of the liver was found. In this case, the lymphoid myelofibrosis seen on bone marrow biopsy may be considered as a manifestation of "discordant" bone marrow histology related to high grade lymphoma. With respect to the cyclic clinical course, a possible role of apoptotic mechanisms in the physiopathology of this disorder is reviewed.

Following conventional chemotherapy, eight myeloma patients presenting with advanced tumor stages were treated with an intensified high-dose regimen and autologous peripheral blood stem cell transplantation. High-dose chemotherapy consisted of idarubicin 20 mg/m(2) on days -13, -12 and -11, melphalan 100 mg/m(2) on days -5 and -4 and cyclophosphamide 60 mg/kg (plus mesna 60 mg/kg) on days -3 and -2 (IMC). Seven patients achieved a complete remission or a very good partial remission (reduction of M-component greater than or equal to 90%). There were no toxic deaths. Severe mucositis and fever of unknown origin were seen in all patients. Reversible supraventricular tachycardias without clinical signs of cardiac failure occurred in five patients. One patient developed a persistent deterioration of cardiac function. We surmise that high-dose chemotherapy with IMC is very effective and well tolerated in myeloma patients.

Aggressive chemotherapy of leukemia increases the risk of severe infections during treatment-induced myelosuppression. However, the assessment of an infectious origin of neutropenic fever is often difficult. Leukocyte adhesion molecules such as E-selectin, intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) are involved in early inflammatory response. We studied plasma concentrations of their soluble isoforms during 48 treatment courses with myeloablative chemotherapy in 32 leukemic patients. There were 35 febrile episodes during neutropenia. Pneumonia was clinically and microbiologically documented in 15 cases, six had proven infections but normal chest radiograph, and 14 were classified as fever of unknown origin. Longitudinal studies revealed a sustained increase of sICAM-1 plasma levels associated with pneumonia. Increase of sICAM-1 plasma levels distinguished patients with pneumonia from those with fever not related to pneumonia (positive predictive value 0.87, negative predictive value 0.94). Plasma levels of sICAM-1 were elevated in both, fungal and non-fungal pneumonia. Increases of sICAM-1 paralleled first radiographic evidence of pulmonary infiltrations in most cases. In contrast, no elevation of sVCAM-1 or sE-selectin was documented during febrile events prior to recovery of leukocyte counts.

Patients undergoing chemotherapy regimens for hematologic malignancies are prone to develop unusual and potentially life-threatening infections during periods of leukopenia- induced immunosuppression. We report the case of a woman who received consolidation chemotherapy for acute lymphocytic leukemia and acquired necrotizing Pseudomonas aeruginosa blepharoconjunctivitis of the right eye during a period of mild leukopenia. The infection led to severe orbital and periorbital inflammation, spreading down to the neck. High-dose antibiotic treatment with ceftazidime and tobramycin combined with granulocyte cell-stimulating factor cleared the infection after several days, but plastic surgery was needed to restore normal eye closure.

The spread of leukemia extends from mobilization of leukemic blast cells from the bone marrow to extramedullary tissue infiltration. Migration of leukemic blasts resembles that of neutrophils and may be regulated by activated endothelial cells via endothelial adhesion molecules such as E-selectin, VCAM-1 and ICAM-1. Plasma levels of soluble adhesion molecules may therefore indicate interaction between leukemic blasts and endothelium, and may be related to leukemic cell mass or subtype of leukemia. In this study, plasma levels of soluble E-selectin, VCAM-1 and ICAM-1 were analyzed in 40 untreated patients with acute leukemia (35 ANLL, five ALL). Plasma concentrations of all three receptors were significantly elevated when compared to healthy controls (P = 0.006, P = 0.0001, and P = 0.0001, respectively) but demonstrated high interindividual variations among leukemic patients. sE-selectin but not sVCAM-1 and sICAM-1 levels correlated with peripheral leukocyte and blast cell counts. Increased levels of either sE-selctin or sVCAM-1 were present in 32 out 40 leukemic patients (80%). FAB subgroups differed in levels of sVCAM-1. The highest levels were measured in acute myelomonocytic and lymphoblastic leukemia, ie in leukemia subtypes with a high incidence of extramedullary blast cell infiltration.

Intravenous amphotericin B (AmB) is the most potent drug for treatment of systemic fungal infections in leukemic patients. However, use of this drug is often limited by renal side effects and acute toxicity (fever, chills, nausea, vomiting). A far better tolerance has been reported with the use of AmBisome, a liposomal preparation of AmB, but this formulation is extremely expensive. In search of a cheaper AmB preparation with a better tolerance than conventional AmB, french scientists recently reported that AmB mixed in fat emulsion (Intralipid) has a significantly better tolerance profile compared to conventional AmB (Caillot et al., 1992, Chavanet et al., 1992). Our pilot study was performed to get information about the tolerance of the three different AmB preparations in individual patients.

Stark erniedrigte Thrombozytenzahlen führen bei autoimmunthrombozy-topenischer Purpura zu einer latenten Blutungsbereitschaft, die bei etwa 2-10% aller erwachsenen Patienten zu schweren intrazerebralen Blutungen führen kann. Durch Gabe von polyvalenten Immunglobulinpräparaten in einer Dosis von 1 g/kg Körpergewicht an 2 aufeinanderfolgenden Tagen kommt es zu einem raschen, jedoch leider nur vorübergehenden Anstieg der Thrombozytenzahlen. Verminderte Volumenbelastung und kürzere Infusionszeiten könnten gerade für ältere Patienten eine Verbesserung dieser Therapieform darstellen. In einer Pilotstudie an 12 Patienten mit Autoimmunthrombozytopenie verglichen wir Effektivität und Verträglichkeit einer neuen 10%igen Immunglobulinpräparation mit dem konventionellen 5 %igen Präparat (Bayer AG, Biologische Präparate, Leverkusen, Deutschland). Patienten mit neu diagnostizierter oder rezidivierter Immunthrombozytopenie wurden zwischen den beiden Präparaten randomisiert, wenn die Thrombozytenzahl unter 20 × 109/1 lag oder eine klinisch manifeste Blutungsneigung bestand. Zwölf Patienten (2 männliche, 10 weibliche) zwischen 25 und 86 Jahren wurden entweder mit dem 5 %igen oder dem 10 %igen IgG-Präparat behandelt. Acht Patienten wiesen Rezidive der Immunthrombozytopenie auf, und 6 Patienten waren mit Kortikosteroiden vorbehandelt. Evaluation von Blutungszeichen und Blutbildkontrollen wurden am 1.-7. sowie am 14. Tag durchgeführt. Während der Infusion erfolgten alle 10 min Messungen der Körpertemperatur und Erfassung potentieller Nebenwirkungen. Bei alien Patienten lag die Thrombozytenzahl 48 h nach Infusionsbeginn über 50 × 109/l, und die Blutungsneigung sistierte. Die beiden Präparate unterschieden sich weder in der Wirkung noch in den potentiellen Nebenwirkungen voneinander. In jeder Behandlungsgruppe trat jeweils am zweiten Behandlungstag eine minderschwere Nebenwirkung auf (Kopfschmerz bzw. Übelkeit). Die Infusionszeit ließ sich durch Verwendung der 10%igen Präparation um durchschnittlich 17% verkürzen, und das Infusionsvolumen wurde halbiert. Aufgrund der Ergebnisse dieser Pilotstudie schließen wir, daß sowohl die 5 %ige als auch die 10%ige Immunglobulinpräparation in der Behandlung der Immunthrombozytopenie im Erwachsenenalter wirksam ist und daß beide Präparate gleich gut vertragen werden.

Very low platelet counts in autoimmune thrombocytopenia cause a bleeding tendency that may result in lethal intracerebral hemorrhage in 2-10% of adult patients. Fast but transient recovery of platelet counts may be achieved with application of i. v. immunoglobulins in a dosage of 1 g/kg body weight on 2 consecutive days. A reduction of the fluid volume in this setting may be beneficial for elderly patients and also reduces the time needed for infusion. In a pilot study on 12 patients with autoimmune thrombocytopenia, we thus compared safety and efficacy of a new 10% i.v. immunoglobulin preparation with a standard 5% preparation (Bayer AG, Biologische Praparate, Leverkusen, Deutschland). Patients with newly diagnosed or recurrent autoimmune thrombocytopenia were randomized between the two treatment arms if they had platelet counts below 20 x 10(9)/l or clinically manifest bleeding. Twelve patients (2 male, 10 female) aged between 25 and 86 years were treated either with the 5% or the 10% ivIgG preparation. Eight patients had recurrent thrombocytopenia and 6 patients had been pretreated with corticosteroids. Signs of bleeding and complete blood counts were determined on days 1 to 7, and on day 14. Body temperature and potential side effects were monitored every 10 min during the infusion. 48 h after the start of infusion, all patients had platelet counts of > 50 x 10(9)/l and no more bleeding symptoms. There was no difference in efficacy or tolerance between the two preparations. In each group there was one minor side effect (headache or nausea) on the 2nd day of treatment. The time needed for infusion was reduced by 17% in patients treated with the 10% IgG preparation, and infusion volume was halved. From this pilot study we conclude that both 5% and 10% immunoglobulin preparations are effective and equally well tolerated in the treatment of autoimmune thrombocytopenia in adults.