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Neoangiogenesis has been shown to play an important role in the pathogenesis of acute myeloid leukemia (AML). Autocrine and paracrine secretion of angiogenic and hematopoietic growth factors such as vascular endothelial growth factor (VEGF) and stem cell factor (SCF) in the bone marrow microenvironment may promote proliferation and survival of leukemic blasts. This concept represented the rationale for the initiation of a multicenter phase 2 trial of SU5416, a small molecule inhibitor of phosphorylation of VEGF receptors 1 and 2, c-kit, the SCF receptor, and fms-like tyrosine kinase-3 (FLT3) in patients with advanced AML. Entered into the study were 43 patients with refractory AML or elderly patients not judged medically fit for intensive induction chemotherapy; 42 patients received at least one dose of study drug. Treatment was generally well tolerated, with nausea, headache, and bone pain the most frequent treatment-related side effects. One patient had a morphologic remission (French-American-British [FAB] criteria of complete response without normalization of blood neutrophil and platelet counts) lasting for 2 months. There were 7 patients who achieved a partial response (reduction of blasts by at least 50% in bone marrow and peripheral blood) lasting 1 to 5 months. Patients with AML blasts expressing high levels of VEGF mRNA by quantitative polymerase chain reaction (PCR) had a significantly higher response rate and reduction of bone marrow microvessel density than patients with low VEGF expression consistent with the antiangiogenic effects of SU5416.

Neoangiogenesis has been shown to play an important role in the pathogenesis of acute myeloid leukemia (AML). Autocrine and paracrine secretion of angiogenic and hematopoietic growth factors such as vascular endothelial growth factor (VEGF) and stem cell factor (SCF) in the bone marrow microenvironment may promote proliferation and survival of leukemic blasts. This concept represented the rationale for the initiation of a multicenter phase 2 trial of SU5416, a small molecule inhibitor of phosphorylation of VEGF receptors 1 and 2, c-kit, the SCF receptor, and fms-like tyrosine kinase-3 (FLT3) in patients with advanced AML. Entered into the study were 43 patients with refractory AML or elderly patients not judged medically fit for intensive induction chemotherapy; 42 patients received at least one dose of study drug. Treatment was generally well tolerated, with nausea, headache, and bone pain the most frequent treatment-related side effects. One patient had a morphologic remission (French-American-British [FAB] criteria of complete response without normalization of blood neutrophil and platelet counts) lasting for 2 months. There were 7 patients who achieved a partial response (reduction of blasts by at least 50% in bone marrow and peripheral blood) lasting 1 to 5 months. Patients with AML blasts expressing high levels of VEGF mRNA by quantitative polymerase chain reaction (PCR) had a significantly higher response rate and reduction of bone marrow microvessel density than patients with low VEGF expression consistent with the antiangiogenic effects of SU5416.

We evaluated toxicity, engraftment, chimerism, graft-versus-host disease (GVHD), and response to a dose-reduced allograft after cytoreductive autografting in 17 patients with advanced stage II/III multiple myeloma (MM). After autografting with melphalan (200 mg/m2) the patients received after a median interval of 119 days (range 60-210) a dose-reduced regimen consisting of fludarabine (180 mg/m2), melphalan (100 mg/m2), and antithymocyte globulin (3 × 10 mg/kg) followed by allografting from related (n = 7), mismatched related (n = 2), or unrelated (n = 8) donors to induce a graft-versus-myeloma effect. After dose-reduced allografting all patients became neutropenic (< 0.2 × 109/L) for at least 8 days. All patients engrafted with a median time for leukocyte (> 1 × 109/L) and platelet (> 20 × 109/L) counts of 16 (range, 11-24) and 23 days (range, 12-43), respectively. Complete donor chimerism was detected after a median of 30 days (range, 19-38). Acute GVHD stage II occurred in 4 patients (25%) and grade III GVHD in 2 patients (13%). Chronic GVHD developed in 40% of the patients, but only 1 patient experienced extensive chronic GVHD requiring further immunosuppressive therapy. Two patients died of alveolar hemorrhage and pneumonia, resulting in a day 100 mortality rate of 11%. The rate of complete remission with negative immunofixation increased from 18% after autografting to 73% after allografting. After a median follow-up of 17 months after autologous and 13 months after allogeneic transplantation 13 patients are alive and 12 of them free of relapse or progression. The tandem auto-allotransplant protocol is highly active and provides rapid engraftment with complete donor chimerism and tolerable toxicity.

We evaluated toxicity, engraftment, chimerism, graft-versus-host disease (GVHD), and response to a dose-reduced allograft after cytoreductive autografting in 17 patients with advanced stage II/III multiple myeloma (MM). After autografting with melphalan (200 mg/m2) the patients received after a median interval of 119 days (range 60-210) a dose-reduced regimen consisting of fludarabine (180 mg/m2), melphalan (100 mg/m2), and antithymocyte globulin (3 × 10 mg/kg) followed by allografting from related (n = 7), mismatched related (n = 2), or unrelated (n = 8) donors to induce a graft-versus-myeloma effect. After dose-reduced allografting all patients became neutropenic (< 0.2 × 109/L) for at least 8 days. All patients engrafted with a median time for leukocyte (> 1 × 109/L) and platelet (> 20 × 109/L) counts of 16 (range, 11-24) and 23 days (range, 12-43), respectively. Complete donor chimerism was detected after a median of 30 days (range, 19-38). Acute GVHD stage II occurred in 4 patients (25%) and grade III GVHD in 2 patients (13%). Chronic GVHD developed in 40% of the patients, but only 1 patient experienced extensive chronic GVHD requiring further immunosuppressive therapy. Two patients died of alveolar hemorrhage and pneumonia, resulting in a day 100 mortality rate of 11%. The rate of complete remission with negative immunofixation increased from 18% after autografting to 73% after allografting. After a median follow-up of 17 months after autologous and 13 months after allogeneic transplantation 13 patients are alive and 12 of them free of relapse or progression. The tandem auto-allotransplant protocol is highly active and provides rapid engraftment with complete donor chimerism and tolerable toxicity.

Rituximab (IDEC-C2B8) is a chimeric antibody that binds to the B-cell surface antigen CD20. Rituximab has significant activity in follicular non-Hodgkin lymphomas. Much less is known about the effects in chronic lymphocytic leukemia (CLL). We have initiated a phase II trial to evaluate the efficacy and safety of rituximab in patients with CD20+ pretreated CLL. To avoid the rituximab-associated toxicity, we restricted the tumor cell load, as measured by the number of circulating lymphocytes and the spleen size, in the first 2 cohorts of patients included in the study. Patients received 4 intravenous infusions of 375 mg/m2 once a week over a period of 1 month. Of the 28 patients evaluable for response, 7 patients showed a partial remission (National Cancer Institute criteria) lasting for a median of 20 weeks, with 1 patient still in remission after 71 weeks. Based on lymphocyte counts only, we found at least a 50% reduction of lymphocyte counts lasting for at least 4 weeks in 13 (45%) of 29 patients. Fifteen patients from 3 institutions were monitored for the immunophenotype profile of lymphocyte subsets. The number of CD5+CD20+ cells decreased significantly and remained low until day 28 after therapy. T-cell counts were not affected. With the exception of one rituximab-related death, adverse events in the remaining patients were mild. The results suggest that rituximab has clinical activity in pretreated patients with B-CLL. Toxicity is tolerable. Response duration after withdrawal of rituximab is rather short. Therefore, other modes of application and the combination with other agents need to be tested.

Rituximab (IDEC-C2B8) is a chimeric antibody that binds to the B-cell surface antigen CD20. Rituximab has significant activity in follicular non-Hodgkin lymphomas. Much less is known about the effects in chronic lymphocytic leukemia (CLL). We have initiated a phase II trial to evaluate the efficacy and safety of rituximab in patients with CD20+pretreated CLL. To avoid the rituximab-associated toxicity, we restricted the tumor cell load, as measured by the number of circulating lymphocytes and the spleen size, in the first 2 cohorts of patients included in the study. Patients received 4 intravenous infusions of 375 mg/m2once a week over a period of 1 month. Of the 28 patients evaluable for response, 7 patients showed a partial remission (National Cancer Institute criteria) lasting for a median of 20 weeks, with 1 patient still in remission after 71 weeks. Based on lymphocyte counts only, we found at least a 50% reduction of lymphocyte counts lasting for at least 4 weeks in 13 (45%) of 29 patients. Fifteen patients from 3 institutions were monitored for the immunophenotype profile of lymphocyte subsets. The number of CD5+CD20+cells decreased significantly and remained low until day 28 after therapy. T-cell counts were not affected. With the exception of one rituximab-related death, adverse events in the remaining patients were mild. The results suggest that rituximab has clinical activity in pretreated patients with B-CLL. Toxicity is tolerable. Response duration after withdrawal of rituximab is rather short. Therefore, other modes of application and the combination with other agents need to be tested.

Between 1981 and 1988, thirty-nine patients with acute myeloid leukemia (AML) following a de novo myelodysplastic syndrome (n-MDS) were studied cytogenetically. The chromosomal aberration rate was 59%. The anomalies most often found were: complex (four or more) aberrations (n = 6), a 5q- chromosome (n = 6), monosomy 7 or a 7q- chromosome and trisomy 8 as the sole defect (n = 3). Incidence and types of chromosomal aberrations were approximately the same as in myelodysplastic syndromes and in 191 patients with de novo AML studied in our laboratory during the same period. But the cytogenetic pattern in AML post de novo MDS also shared certain similarities with chromosomal findings in 35 patients with secondary, therapy-induced (t) AML/MDS. In both these types of acute leukemia primary changes such as t(8;21), t(15;17) and inv (16) were not found; the frequency of AA-Karyotypes was high (70 and 66%) and the incidence of -5,5q- in AML post de novo MDS was more comparable with that found in t-AML/MDS than in de novo AML. Thus the chromosomal patterns seen in AML post de novo MDS indicate that these leukemias share similarities with both de novo and t-AML not only clinically but also cytogenetically.

Zusammenfassung An 163 Venenblutproben mit deutlichen Leukozytosen (20 000 bis 172000 Zellen je mm3) lie\en sich Verschleppungen von 400 bis 22 000 Leukozyten bis in die 3. Zählung der nachfolgenden Proben (200 bis 9 300 Zellen/mm3) nachweisen. Auch nach 41 Normalbluten und geringen Leukozytosen (6 700 bis 17 700 Zelen/mm3) wurde bei extremen Leukopenien (<2000 Zellen/mm3) das richtige Ergebnis noch um 500 bis 1000 Zellen überschritten. An vier weiteren Geräten verschiedener Laboratorien waren Zellverschleppungen in unterschiedlichem Ausma\ reproduzierbar. Im Vergleich zu Vollblutproben wurden nur minimale Verschleppungen in nachfolgender isotonischer Salzlösung gefunden. Die ursächlich noch ungeklärte erhebliche Streuung des Verschleppungskoeffizienten zwischen 1,7 und 16,2% (Mittelwert 7,1%) verbot eine rechnerische Fehlerkorrektur. Irrtümlich zu hohe Leukoztenzahlen wurden durch mindestens zwei Wiederholungszählungen sicher vermieden.

Summary l hour after i. v. infusion of colloidal iron in iron deficient subjects uniform phagosomal iron granules were observed in macrophages and endothelial cells of several organs. 7 to 10 days later transformation into ferritin could be visualized in macrophages only. Now, these cells showed diffuse iron staining of the cytoplasm due to dispersed ferritin molecules. Polymorphous lysosomes contained densely packed particles from still unchanged ferric hydroxide to paracristalline ferritin. The macrophageal iron was mobilizable in few days to several weeks. The uniform lysosomal iron granules of endothelial cells disappeared after 1 to 2 years. Endothelial iron siderosis without previous i.v. iron application was a frequent finding in pernicious anaemia and iron overload of diverse origin.

Zusammenfassung Durch ein einfaches Kontrollprogramm für den Coulter S lie\en sich zwei Reagen-zienfehler von klinischer Relevanz aufdecken: Zu hohe HÄmatokritwerte infolge einer fehlerhaften Isoton®-Charge gingen mit einer MCHC-Erniedrigung nativer Blutproben, nicht aber des stabilisierten 4 C-Blutes® einher. FÄlschlich überhöhte Leukozytenwerte durch ungenügend aufgelöste Riesenthrombozyten und Thrombozytenaggregate lie\en sich auf verÄnderte Lyse-S®-Chargen zurückführen, nachdem Vergleiche im Coulter F mit Zaponin® und in der ZÄhlkammer um bis zu 10000 Zellen niedrigere Werte ergeben hatten.

A total of 68 adult patients with B-cell acute lymphoblastic leukemia (B-ALL) were treated in three consecutive adult muhicenter ALL studies. The diagnosis of B-ALL was confirmed by L3 morphology and/or by surface immunoglobulin (Slg) expression with >25% blast cell infiltration in the bone marrow (BM). They were characterized by male predominance (78%) and a median age of 34 years (15 to 65y) with only 9% adolescents (15 to 20y), but 28% elderly patients (50 to 65y). The patients received either a conventional (N = 9) ALL treatment regimen (ALL study 01/81) or protocols adapted from childhood B-ALL with six short, intensive 5-day cycles, alternately A and B. In study B-NHL83 (N = 24) cycle A consisted of fractionated doses of cyclophosphamide 200 mg/m2for 5 days, intermediate-dose methotrexate (IdM) 500 mg/m2(24 hours), in addition to cytarabine (AraC), teniposide (VM26) and prednisone. Cycle B was similar except that AraC and VM26 were replaced by doxorubicin. Major changes in study B-NHL86 (N = 35) were replacement of cyclophosphamide by ifosphamide 800 mg/m2for 5 days, an increase of IdM to high-dose, 1,500 mg/m2(HdM) and the addition of vincristine. A cytoreductive pretreatment with cyclophosphamide 200 mg/m2, and prednisone 60 mg/m2, each for 5 days was recommended in study B-NHL83 for patients with high white blood cell (WBC) count (>2,500/m2) or large tumor burden and was obligatory for all patients in study B-NHL86. Central nervous system (CNS) prophylaxis/treatment consisted of intrathecal methotrexate (MTX) therapy, later extended to the triple combination of MTX, AraC, and dexamethasone, and a CNS irradiation (24 Gy) after the second cycle. Compared with the ALL 01/81 study where all the patients died, results obtained with the pediatric protocols B-NHL83 and B-NHL86 were greatly improved. The complete remission (CR) rates increased from 44% to 63% and 74%, the probability of leukemia free survival (LFS) from 0% to 50% and 71% (P= .04), and the overall survival rates from 0% to 49% and 51% (P= .001). Toxicity, mostly hematotoxicity and mucositis, was severe but manageable. In both studies B-NHL83 and B-NHL86, almost all relapses occurred within 1 year. The time to relapse was different for BM, 92 days, and for isolated CNS and combined BM and CNS relapses, 190 days (P= .08). The overall CNS relapses changed from 50% to 57% and 17%, most probably attributable to the high-dose MTX and the triple intrathecal therapy. LFS in studies B-NHL83 and B-NHL86 was significantly influenced by the initial WBC count < or >50,000/μL, LFS 71% versus 29% (P= .003) and hemoglobin value > or <8 g/dL, LFS 67% versus 27% (P= .02). Initial CNS involvement had no adverse impact on the outcome. Elderly B-ALL patients (>50 years) also benefited from this treatment with a CR rate of 56% and a LFS of 56%. It is concluded that this short intensive therapy with six cycles is effective in adult B-ALL. HdM and fractionated higher doses of cyclophosphamide or ifosphamide seem the two major components of treatment.

1.Anhand eines Untersuchungsgutes von fast 400000 zeichnerisch erfaßten Zellen haben wir die mitotische Wachstumsaktivität von Leber, Lunge, Ösophagus und Magen beim embryonalen und fetalen Hühnchen bestimmt. Die Ergebnisse wurden mit der von Grohmann (1961) für das Myokard ermittelten Mitoserate verglichen. Die Auswertung von drei Keimen pro Entwicklungsstadium darf für eine statistische Analyse als ausreichend angesehen werden.2.Die Brauchbarkeit mehrerer mathematisch-statistischer Methoden zur Analyse von Wachstumsabläufen wurde geprüft (Mittelwerte, Regressions- und Korrelationskoeffizient, ChiQuadrat-Test).3.Das mitotische Wachstum der Leber beginnt am 3. Bebrütungstag mit einer Mitoserate von 1,46%, erreicht am 4. Tag mit 2,04% das Maximum und sinkt anschließend bis auf 0,50% am 14. Tag. Das Ende der Primitiventwicklung ist durch eine Stufe nach dem 7. Tag gekennzeichnet. Zwischen rechter und linker Leberhälfte war kein Wachstumsunterschied festzustellen.4.Die Lungenentwicklung beginnt am 3. Bebrütungstag. Während der Primitiventwicklung weist das Mesoderm eine höhere Mitoserate als das Entoderm auf. Diese steigt von 1,17 auf 1,33% am 4. Tag und sinkt danach bis auf 0,25% am 14. Tag. Die Primitiventwicklung endet mit einer Stufe nach dem 6. Tag. Im Entoderm steigt die Mitoserate von 0,83 auf 1,30% am 5. Tag und hält diese Höhe annähernd bis zum 11. Tag, um dann auf 0,25% (14. Tag) abzufallen.5.Die Ausbildung des Ösophagus setzt am 2. Bebrütungstag ein. Die mitotische Aktivität steigt von 0,68 auf 1,12% (4. Tag), bleibt — mit Ausnahme einer geringen Senkung am 6. Tag — auf Werten zwischen 0,91 und 1,01% und fällt nach dem 10. Tag auf einen Wert von 0,36% am 14. Tag ab. Die Entwicklung des Magens beginnt zwischen dem 3. und 4. Tag. Die Mitoserate steigt auf 1,19 bzw. 1,24% am 5. und 6. Tag, schwankt bis zum 11. Tag zwischen 0,85 und 1,13% und fällt danach mit einer Stufe auf 0,55% am 14. Bebrütungstag.6.Die durchschnittliche Wachstumsaktivität des Myokard liegt zwischen dem 4. und 14. Tag mit 1,94% deutlich über dem entsprechenden Wert von Leber (1,03%), Lungenmesoderm (0,95%), Magen (0,91%), Lungenentoderm (0,88%) und Ösophagus (0,73%).7.Myokard, Leber und Lungenmesoderm zeigen einen gleichartigen Wachstumsverlauf. Die stärkste Wachstumsaktivität fällt mit einem Gipfel am 4. Tag in die Primärphase.8.Lungen-, Ösophagus- und Magenentoderm verkörpern einen anderen Wachsumstyp und zeigen ebenfalls eine einheitliche Entwicklung. Nach einem Mitoseanstieg zum 5./6.Tag wird bis zum 10./11.Tag ein annähernd konstantes Niveau gehalten, worauf sich ein Abfall anschließt. Das stärkste Wachstum liegt in der Postprimärphase.9.Die Bedeutung der erhobenen Befunde für Schädigungsmöglichkeiten des embryonalen und fetalen Organismus und damit für die Entstehung von Mißbildungen wurde diskutiert.

Saussele: ARIAD: Honoraria; BMS: Honoraria, Other: Travel grant, Research Funding; Pfizer: Honoraria, Other: Travel grant; Novartis Pharma: Honoraria, Other: Travel grant, Research Funding. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Scheid:Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Baerlocher:Geron Corporation: Research Funding; Novartis: Research Funding. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Müller:BMS: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Hochhaus:ARIAD: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Pfirrmann:BMS: Consultancy, Honoraria; Novartis Pharma: Consultancy, Honoraria. Baccarani:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; NOVARTIS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ARIAD Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hehlmann:BMS: Consultancy; Novartis Pharma: Research Funding.