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Expression of stem cell phenotype (CD34) and multidrug resistance (MDR) on blast cells of 49 untreated patients with primary myelodysplastic syndromes (MDS) was studied by means of the alkaline phosphatase antialkaline phosphatase technique (APAAP). In 29 patients (59%) CD34 and in 19 patients (39%) MDR positivity was found. Both immunocytological markers showed a strong positive correlation (p<0.0005) and MDR expression was only detectable in CD34 positive cases. When comparing CD34 and MDR expression with well established prognostic parameters, medullary bone marrow (BM) blast percentage was found to be the sole variable which correlated with expression of both cell surface markers. CD34 and MDR negative patients had a better prognosis although only the difference between CD34 positive and CD34 negative cases reached statistical significance. Regarding the prognostic value of immunocytological results and other clinical and hematological parameters medullary blast cell infiltration remained the strongest predictive variable for survival and AML transformation. In 6 patients sequential immunocytological analysis during progression of disease were performed. In contrast to stable CD34 expression a marked increase in MDR expression after AML development could be noted in 2 cases.

Coexpression of myeloid, B-, and T-lineage associated markers was found in a patient with morphologically and cytochemically undifferentiated acute leukemia. Surface marker analysis using two-color immunofluorescence staining characterized blast cells to express CD34, CD38, CD117, and class II antigens, coexpressing TdT, CD4, CD7, CD13, CD19, and CD33. Cytoplasmic expression of myeloperoxidase, CD3, and CD22 could not be demonstrated. Monosomy for chromosome 7 was found by cytogenetic analysis. The absence of clonal rearrangements of immunoglobulin or T-cell receptor genes was shown by Southern blot analysis. Using a 3H-thymidine incorporation assay, DNA synthesis of leukemic blasts could be stimulated by IL-3, IL-6 and G-CSF in vitro. The present case did not offer specific criteria of lineage commitment. Corresponding to an equivalent counterpart in normal hematopoiesis, the involved cell population may reflect an early, most immature developmental stage within a multipotent progenitor cell compartment.

Treatment of myelodysplastic syndromes (MDS) with recombinant human erythropoietin (Epo) is successful in only 10% to 25% of patients. We performed a pilot study in 10 anaemic patients with MDS to examine whether sequentially applied recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) and Epo improves haemoglobin levels and/or reduces red blood cell transfusion requirements. Morphological diagnoses of patients were refractory anaemia (RA) in 3 cases, RA with ring sideroblasts in 3 cases and RA with excess blasts in 4 cases. GM-CSF was given subcutaneously at a dose of 150 micrograms/m2/d during the initial 10 days. From day 11, Epo was administered by subcutaneous injections for 8 weeks at a dose of 100 U/kg/d and subsequently at an escalated dose of 200 U/kg/d in 3 patients. Changes in reticulocyte counts, haemoglobin levels, RBC support and ferrokinetic parameters were compared with pretreatment values. Two out of 8 evaluable patients showed a rise in haemoglobin levels at week 8 and 10, respectively, and lost their transfusion dependency for a period of 13 and 27 weeks. In 1 patient, haemoglobin level increased only after dose escalation of Epo (200 U/kg/d). Leukocyte counts remained uneffected by treatment with Epo, while 1 patient showed a 4-fold increase in platelet numbers. Toxicity was mild. Two patients died of pneumonia and global heart failure, respectively, unrelated to growth factor therapy. Based on this pilot study, we conclude that sequential treatment with GM-CSF and Epo does not increase erythroid responses in anaemic patients with MDS. Because of the delayed increase in haemoglobin in both responders, we surmise that the beneficial effects were induced by Epo alone.

Allogeneic BMT provides potential life-saving therapy for a variety of inherited and acquired diseases of the hemopoietic and the immune systems, including malignancies. At the University of Essen more than 800 transplants have been performed during the past 20 years. CML was the most frequent indication for BMT in Essen. Patients transplanted in first chronic phase had a high probability of disease-free survival, whereas patients transplanted with more advanced disease had long-term remission only in a minority of cases. With AML, optimal timing for transplantation remains undetermined. Patients at high risk of chemotherapy failure and relapse may have a better overall chance of long-term disease-free survival and cure if transplanted in first remission. BMT for patients with ALL are generally reserved for patients failing chemotherapy or in first remission with prognostic factors predicting a high risk of failure with chemotherapy alone. Compared with conventional bone marrow harvest, the advantages of mononuclear-blood-cell apheresis will probably change the standard procedure for bone marrow harvest in the future. Since 1995, an increasing number of blood stem cell transplants have been successfully performed in allogeneic transplants at the University of Essen.

We have recently proposed a scoring system for risk assessment in primary myelodysplastic syndromes (MDS). In this score, one point is allocated to each of the following four parameters: bone marrow blasts > or = 5%, LDH > 200 U/l, hemoglobulin concentration < or = 9 g/dl, and platelet count < or = 100 x 10(9)/l. In a published series of 235 untreated patients with primary MDS, three prognostic groups (group A, score 0; group B, score 1 or 2; group C, score 3 or 4) were identified which differed significantly in both survival and rates of leukemic transformation. The present study was undertaken to reexamine the usefulness of our scoring system by applying it to an independent population of 263 newly diagnosed MDS patients. Morphological subtypes were RA in 53 (20%), RARS in 32 (12%), pure sideroblastic anemia (PSA) in 41 (16%), RAEB in 60 (23%), RAEB/T in 34 (13%), and CMML in 43 cases (16%). The predictive value of the Düsseldorf score could be assessed in 244 of 263 patients (initial LDH levels or platelet counts lacking in 19 cases). Forty-two patients were assigned to group A (low risk), 132 to group B (intermediate risk), and 70 to group C (high risk). Two-year cumulative survival was 86% in group A, 57% in group B and 14% in group C. Five-year cumulative survival was 53, 26 and 0%, respectively (p < 0.00005). Cumulative risk of AML 2 years after diagnosis was 3% in group A, 12% in group B, and 41% in group C (p < 0.05). Additional validation of the score was provided by extended follow-up of the initial patient population on which the scoring system was based. Survival curves in this patient population developed as predicted by the score. An important advantage of the Düsseldorf score is its ability to identify high-risk patients among the RA and RARS subgroups, even though by definition medullary blasts are less than 5%. The inclusion of LDH levels as a prognostic parameter also qualifies the Düsseldorf score for a correct assessment of CMML patients. In the new study population, LDH was confirmed as an important prognostic factor. After 2 years, actuarial survival for patients with LDH levels < or = 200 U/l was 61%, compared with 34% for patients with LDH > 200 U/l. Five-year cumulative survival was 32 and 14%, respectively (p < 0.00005).(ABSTRACT TRUNCATED AT 400 WORDS)

Conventional-dose Ara-C (200 mg/m2 d 1-5) combined with idarubicin (12 mg/m2 d 1-3) was employed as remission induction and consolidation therapy in 23 elderly AML patients with a median age of 66 years (range, 60-75) with AML according to the FAB criteria (M1 n = 3, M2 n = 10, M4 n = 6, M5 n = 2, M6 n = 2), eligible for the study. In seven patients earlier MDS had been documented by previous bone marrow aspirates. The CR rate after one induction course was 65% (15/23). Toxicity was acceptable, with four patients dying during the chemotherapy-induced hypoplasia (4/23). Although 80% of the CR patients received two additional cycles of Ara-C and idarubicin as consolidation therapy, only two patients are still in continuous complete remission more than 12 months after achieving CR. The median disease-free survival of the CR patients was 11.5 months and the median survival of the entire group was 10 months. We conclude that conventional dose Ara-C/idarubicin is an effective protocol for inducing complete remission in elderly patients with AML, but that consolidation therapy consisting of two courses of the same regimen does not produce a relevant rate of long-term disease-free survival.

Background: Previous studies have shown that serum levels of deoxythymidine kinase (sTK) provide useful prognostic information in various malignancies, such as Hodgkin's disease, non-Hodgkin's lymphomas, multiple myeloma, and acute myeloid leukemia (AML)., Methods: Using a radioenzyme assay, the authors determined sTK in 146 patients with primary myelodysplastic syndromes (MDS). Morphologic subtypes were refractory anemia (RA) in 18 patients, RA with ring sideroblasts (RARS) in 24, RA with excess of blasts (RAEB) in 41, RAEB in transformation (RAEB/T) in 29, and chronic myelomonocytic leukemia (CMML) in 34., Results: Enzyme levels ranged from 1.1 to 829 U/microliters. One hundred fifteen (79%) patients had elevated sTK levels (more than 5 U/microliters) at the time of diagnosis. In advanced stages of MDS (RAEB, CMML, and RAEB/T) enzyme activities were higher than in early stages (RA and RARS) (P < 0.05). However, sTK levels were not correlated with the percentage of medullary blast cells. Among other parameters tested, the best correlation with sTK was found for serum lactate dehydrogenase (LDH) activity (r = 0.29; P < 0.0005). As shown by life table analysis, sTK activity at diagnosis provided useful information regarding the prognosis of patients. For patients with sTK levels of less than 10 U/microliters, actuarial survival after 2 years was 65%, compared with 33% for those with enzyme values of 10 U/microliters or greater. The 5-year cumulative survival rates were 34% and 14%, respectively (P < 0.0005). However, sTK levels at diagnosis were not useful for predicting transformation to AML. Nine of 61 (15%) patients with sTK of less than 10 U/microliters had AML develop, whereas 15 of 57 (26%) patients with sTK of 10 U/microliters or greater had disease progress to acute leukemia (chi-square, 1.64; P = 0.2)., Conclusions: Considering the lack of correlation with bone marrow blasts, the authors conclude that increased sTK levels in MDS are primarily attributable to intramedullary destruction of hematopoietic precursors and do not reflect the leukemic blast cell burden. This appears similar to the ineffective hematopoiesis of vitamin B12 deficiency, which is associated with elevated levels of sTK and LDH. The data suggest that sTK is a prognostic parameter that can be used to predict the survival of patients with MDS. However, multivariate analysis shows that the predictive value of sTK is not superior to that of LDH.

Considering the beneficial effect of all-trans retinoic acid (ATRA) in acute promyelocytic leukemia (APL), it has been speculated that ATRA might also be useful for treating other hematologic malignancies. To test this hypothesis, we performed a dose-escalating 3-month-trial of ATRA in 15 patients with primary or secondary myelodysplastic syndromes (MDS). Morphologic diagnoses were refractory anemia (RA) in 4, RA with ring sideroblasts (RARS) in 2, RA with excess blasts (RAEB) in 7, and RAEB in transformation (RAEB/T) in 2 cases. Patients included were required to have one or more of the following criteria: transfusion-dependent anemia, pronounced neutropenia (< or = 0.5 x 10(9)/L) or thrombocytopenia (< or = 20 x 10(9)/L), or increasing blast cells in the peripheral blood or bone marrow. Therapy was started at an ATRA dose of 30 mg/m2/d, administered orally as two doses of 15 mg/m2 every 12 hours. The retinoid dose was increased to 60 mg/m2/d after 4 weeks and to 90 mg/m2/d after 8 weeks. Among 14 patients assessable for response, none obtained a complete or partial remission. Three patients had a minor response, manifested by either reduction in transfusion requirements (2 patients) or increase in neutrophil and platelet counts (1 patient). During the study period, 5 patients progressed to more advanced stages of MDS or overt leukemia. Three patients with chromosomal abnormalities receiving ATRA for a period of 10 to 12 weeks retained their cytogenetic marker after completion of treatment. Side effects of ATRA primarily affected the skin and mucous membranes, with 13 of 15 patients having at least low-grade dermatologic toxicity. In 2 cases, treatment had to be prematurely stopped because of intolerable conjunctivitis or progressive neurologic symptoms. These data suggest that ATRA has little effect on MDS. The lack of response of MDS patients, as compared with those with APL, may be attributed to the absence of the t(15;17) translocation that seems to be a prerequisite for clinical efficacy of ATRA.

From a total of 18,416 bone-marrow biopsy reports entered into the Düsseldorf Bone Marrow Registry between 1975 and 1990 those of patients diagnosed as having preleukaemia, myeloid dysplasia, panmyelopathy with hypercellular bone marrow, refractory anaemia, sideroblastic anaemia or smoldering leukaemia were reanalyzed together with patient-data. If the diagnosis of myelodysplastic syndrome (MDS) was confirmed, the original blood and bone-marrow smear was re-examined and classified, 584 cases in all (3.2%). During the same period acute myeloid leukaemia had been diagnosed in 506 patients (2.8%). The average annual incidence of MDS in the Düsseldorf area was 3.65 per 100,000 inhabitants. Over 80% of cases occurred from the age of 60 years, while 7% were younger than 50 years. The sex ratio was the same in all subgroups of MDS, except chronic myelomonocytic leukaemia (male:female ratio 1:1.57). 31 patients (5.3%) had received ionizing radiation and/or cytostatic or immunosuppressive treatment for various underlying diseases before MDS had been diagnosed (secondary MDS). Preceding occupational contact with organic solvents could not be excluded with certainty in 12 patients. These data suggest that MDS is a relatively frequent disease of hematopoiesis among the older age groups. The proportion of secondary (treatment-induced) forms is small and does not explain the recently observed increased incidence.

The clinical course of three patients with acute promyelocytic leukemia receiving all-trans retinoic acid (ATRA) as a single agent is reported. The first two patients were in first and second relapse of their leukemia that had occurred despite maintenance treatment with 13-cis retinoic acid after chemotherapy-induced complete remission (CR). A switch to ATRA was followed by achievement of a CR in two patients. The third patient received ATRA as first-line therapy. Two patients experienced thromboembolic complications during the phase of ATRA-induced leukocytosis. One of them died of pulmonary embolism on day 16 of treatment. The two responding patients who did not receive consolidation chemotherapy relapsed after 6 and 9 months, respectively. Increase of the ATRA dose failed to induce a new remission.

Medullary dyserythropoiesis with reduced production of erythrocytes is an early and consistent feature of myelodysplastic syndromes (MDS). The mechanism underlying the disturbed red cell proliferation and maturation is presently unknown. In order to study the role of erythropoietic growth factors, we determined by radioimmunoassay the serum concentrations of immunoreactive erythropoietin (Epo) in 42 non-transfused patients with primary and secondary MDS. Their median hemoglobin concentration at the time of Epo measurement was 9.1 g/dl (range, 5.7-14.6). Compared with the control group, 83% of the MDS patients had increased serum Epo levels, ranging from 26-4530 mU/ml. Although in the entire patient population an inverse relationship between serum Epo and hemoglobin concentrations was noted (r = -0.35; p = 0.02), Epo titers differed markedly between patients at comparable degrees of anemia. In 7 patients presenting with a hemoglobin concentration between 5.9 and 11.9 g/dl, excessive elevations of Epo levels (greater than 500 mU/ml) were found. In contrast to previous observations, serum Epo concentrations were not shown to correlate with the percentage of erythroblasts in the bone marrow. There was, however, a significant relationship between the Epo activity and the degree of medullary dyserythropoiesis, as assessed by morphological criteria (p less than 0.01). From these data we conclude that the anemia in MDS is not due to an endogenous Epo deficiency. The marked variability of Epo production in these disorders is not fully explained by the degree of anemia, but may also reflect inherent abnormalities of the myelodysplastic erythropoiesis.

Eight neutropenic patients with acute lymphocytic or nonlymphocytic leukemia had septicemia due to different strains of Streptococcus mitis (St. mitis), a microorganism not commonly recognized as a special pathogen in leukemic patients. Four of the patients had been treated with high-dose cytosine arabinoside as part of the cytostatic regimen, six had a central venous line and four patients had oral lesions prior to the infection. Selective gut decontamination consisted of co-trimoxazole/colistin in five patients and quinolones in three patients. The first three patients died, either due to interstitial pneumonia with the adult respiratory distress syndrome (ARDS), or due to infection-triggered disseminated intravascular coagulation despite prompt empiric antibiotic therapy including vancomycin. The other patients improved after empiric supplementation of penicillin G (30 Mega/day) to the antibiotic regimen. Beginning ARDS in two of these patients dramatically responded to high-dose steroids. We conclude that St. mitis is a major pathogen in neutropenic leukemic patients. Infection appears to occur independently of acute leukemic cell type, regimen of selective gut decontamination, venous access, visible oral lesions or treatment with high-dose cytosine arabinoside. The clinical course of our patients raises questions about the value of commonly recommended empiric antibiotic regimens, which were clearly ineffective to control infections with St. mitis in this patient group. Our data indicate that immediate antibiotic therapy with penicillin G is indicated and may be life-saving for suspected St. mitis infections in neutropenic leukemic patients.

In this open, controlled, randomized multi-clinic trial, monotherapy with imipenem/cilastatin was compared to amikacin plus piperacillin as empiric antibacterial therapy in 210 neutropenic cancer patients. Of patients randomized, 53 (25%) had bacteriologically documented infections and of those 30 had septicemia. A further 80 patients (38%) were evaluable for clinical efficacy but did not have documented infections. Seventy-seven patients (37%) were non-evaluable due to effective antibiotic treatment before the trial, early institution of other antibiotics during the trial, verified non-bacterial infections, no neutropenia or other reasons. There were no significant differences in terms of efficacy between imipenem/cilastatin and amikacin plus piperacillin but a consistent trend towards higher rates of clinical cure or improvement and of elimination of causative pathogens was noted in the imipenem/cilastatin group. In patients who were severely neutropenic (less than 0.1 x 10(9) granulocytes/l), similar cure rates were obtained in the two treatment groups--again with a tendency towards better results in the imipenem/cilastatin group. Among evaluable patients with septicemia, one patient in the imipenem/cilastatin group had persistent Staphylococcus aureus bacteremia during treatment. Five patients in the amikacin plus piperacillin group had persistent bacteremia during treatment; all but one (a Pseudomonas aeruginosa) caused by strains resistant to amikacin or piperacillin. Clinical and laboratory adverse effects were mild in the imipenem/cilastatin group although nausea was significantly more common than in the amikacin plus piperacillin group. Among patients on amikacin plus piperacillin, one died in renal failure, possibly related to treatment. Drug-related serious adverse events were reported in two additional amikacin plus piperacillin patients; one with drug fever and one with hearing loss. Microbiological adverse effects occurred in similar frequencies in the two groups. It is concluded that imipenem/cilastatin is a promising candidate for monotherapy of bacterial infections in neutropenic cancer patients.