Long-term follow-up of patients >or=60 yr old with acute myeloid leukaemia treated with intensive chemotherapy.

It is still controversial how to treat elderly patients with acute myeloid leukaemia (AML), and results have been poor with most regimens. We report the long-term results of a randomised study performed by the Leukaemia Group of Middle Sweden during 1984-88 comparing two intensive chemotherapeutic drug combinations. Ninety patients >or=60-yr old with untreated AML were randomly allocated to treatment with daunorubicin, cytosine arabinoside (ara-C), and thioguanine (TAD) (43 patients) or a combination in which aclarubicin was substituted for daunorubicin (TAA) (47 patients). Forty-four patients (49%) entered complete remission (CR), 22/43 (51%) in the TAD group and 22/47 (47%) in the TAA group (ns). The CR rate in patients 70 yr 14/48 (29%) (P<0.0001). Early death within 30 d after treatment initiation was more often seen in patients >70 yr than in patients or=10 yr after inclusion of the last patient, 5/90 patients (one in the TAD group and four in the TAA group, respectively) were still alive, four in continuous complete remission and one in second complete remission. Thus, both treatment regimens appear to have similar efficacy, with a relatively high complete remission rate, and a reasonable survival as compared to other studies including some long-term survivors. However, early deaths are still numerous, particularly in patients above 70 yr of age, and the relapse rate is substantial.

Intensive treatment in order to minimize the Ph-positive clone in CML. Danish-Swedish CML Group.

With the rationale that a significant reduction of the malignant clone in CML might prolong time to metamorphosis, intensive treatment was given to patients < or = 55 years. Six months of hydroxyurea and high dose interferon-alpha (IFN-alpha) was followed by one to three courses of intensive chemotherapy. Patients who had a donor were allotransplanted and patients who became Ph-negative in bone marrow were autotransplanted. On 1 May 1995, 160 patients were registered in the study. Fifty-one percent of the patients who received six months IFN-alpha and hydroxyurea had a significant Ph-reduction and 5% became Ph-negative. The corresponding figures after two intensive chemotherapy courses were 47 and 28%, respectively. Twenty-seven of 30 autotransplanted patients have been analysed for Ph. Seventeen have relapsed cytogenetically, while ten are Ph-negative 1-64 + months after ABMT. BMT was performed in 59 patients. The actuarial 6-year survival from diagnosis of all 160 registered patients is 68%, which seems to be better than for age-matched historical controls.

Intensive treatment in order to minimize the Ph-positive clone in chronic myelogenic leukemia.

Several studies indicate that interferon (IFN) treatment, intensive chemotherapy and autologous bone marrow transplantation (ABMT) effectively reduce the Ph-positive clone in Chronic Myelogenic Leukemia (CML). In the present study on patients < or = 55 years, we have combined these three treatment modalities. The aim of the study was to eliminate or minimize the Ph-positive clone to see whether a status of minimal residual or Ph-negative disease could be maintained for a longer period of time. After diagnosis, patients received interferon (IFN-a-2b) and hydroxyurea (HU) to keep the white blood cell (WBC) and platelet count below 2-4 and 100-150 x 10(9)/l, respectively. After six months of treatment, Ph-analysis was performed. Patients with Ph-positive cells in bone marrow then received 1-3 courses of intensive chemotherapy. In patients Ph-negative after two courses, bone marrow was harvested and used for ABMT. After a third course, patients with up to 50% Ph-positive metaphases were accepted for ABMT. As of January 1, 1993, 97 patients were registered in the study. Six months of IFN+HU reduced the percentage of Ph-positive metaphases in 57% of the patients (7% became Ph-negative). The corresponding figures after two intensive cytotherapies were 70% (40% Ph-negative). Eighteen patients were autotransplanted. Seven have relapsed with Ph-positivity 3-22 months after ABMT, while nine are Ph-negative at 1-32+ months after ABMT (two not yet analyzed). Seventeen patients are alive and well, while one died one month after ABMT due to interstitial pneumonia.(ABSTRACT TRUNCATED AT 250 WORDS)

Successful treatment of hepatosplenic candidiasis with a liposomal amphotericin B preparation.

The case of a granulocytopenic patient with acute undifferentiated leukaemia and hepatosplenic candidiasis who was refractory to conventional deoxycholate amphotericin B (AmpB) and 5-flucytosine therapy is reported. He experienced severe AmpB-related side-effects, and was subsequently successfully treated with a pharmaceutical preparation of AmpB (5.7 g) entrapped in sonicated liposomes, composed of lecithin, cholesterol and stearylamine in a molar ratio of 4:3:1. Three months later, during maintenance chemotherapy, liposomal AmpB (5.1 g) was reinstituted due to the finding of biopsies positive for Candida albicans at bronchoscopy. After healing of the patient's fungal infection a left upper lobe resection was performed, which showed advanced fibrosis with signs of inflammation, but no evidence of fungal disease. Since no acute side-effects and only moderate hypokalaemia were observed, it appears that liposomal AmpB is superior to conventional AmpB treatment in granulocytopenic patients with hepatosplenic candidiasis and unbearable therapy-related side-effects.

Storage of platelets in a new plastic container. Polyvinyl chloride plasticized with butyryl-n-trihexyl citrate.

The effect of storage of platelets in a new polyvinyl chloride (PVC) plastic material with a butyryl-n-trihexyl citrate (BTHC) plasticizer (PL 2209) was evaluated. The PL 1240 container, i.e. PVC plastic with a different plasticizer, tri-(ethylhexyl)-tri-mellitate, was used as a reference. Measurements of pH, pO2, pCO2, glucose, lactate, adenosine triphosphate, total adenine nucleotide content, lactate dehydrogenase and platelet factor 4 (PF4) were made during 5 days of storage. Similar results were noted comparing PL 2209 and PL 1240. Differences in pO2 and pCO2 indicate greater gas permeability in PL 2209 than in PL 1240. Significantly higher PF4 levels were found in PL 2209, but the difference could not be attributed to the PL 2209 container itself. Paired autologous reinfusion studies (111Indium) of 6 normal donors gave mean recovery values after 5-day storage of 41.1 +/- 7.4% (PL 2209) and 45.5 +/- 7.7% (PL 1240), t1/2 66 +/- 13 and 75 +/- 5 h, survival time (linear model) 6.3 +/- 1.0 and 6.8 +/- 0.7 and survival time (multiple-hit model) 6.0 +/- 0.7 and 6.5 +/- 0.4 days, respectively. Only the difference in survival time (multiple-hit) was significantly higher in PL 1240. The corrected count increments at 12-24 h following transfusion were 13,300 +/- 10,800 (PL 2209) and 13,600 +/- 11,600 (PL 1240) with no statistically significant difference found. These results indicate PL 2209 as an equivalent alternative to PL 1240 for the 5-day storage of platelets.

A Randomized Comparison of Doxorubicin and Doxorubicin-DNA in the Treatment of Acute NonLymphoblastic Leukemia.

In the light of previous findings that treatment of leukemia patients with DNA-linked doxorubicin gave higher doxorubicin concentrations in leukemic cells than treatment with doxorubicin alone, the Leukemia Group of Middle Sweden performed a randomized clinical trial to compare the effects of doxorubicin and doxorubicin-DNA in patients with acute non-lymphoblastic leukemia. One hundred and twenty consecutive patients within the age range 15 to 60 years were randomized to one of three treatment groups. In two of these, remission induction treatment was performed with prednisolone, vincristine, ara-C and thioguanine combined with either doxorubicin or doxorubicin-DNA. Patients entering a complete remission received intensive consolidation during 16 months with 4 courses each of doxorubicin (+/ - DNA)/ara-C, doxorubicin (+/ - DNA)/azacytidine, ara-C and amsacrine. The third treatment group followed a protocol from a previous study with daunorubicin and ara-C for induction therapy and a less intensive maintenance therapy. No further patients were assigned to this "control" group after 3 years or to the two other groups after 6 years. This report is based on a follow-up 31 months thereafter. The overall rate of complete remission was 67% and the mean time to complete remission was 71 days, with no differences between the treatment groups. Patients treated with the doxorubicin-DNA conjugate had a significantly longer survival [median for all patients 27.2 months (p < 0.01) and for patients in CR 47.0 months (p < 0.025)] and longer duration of first remission (median 23.6 months, p < 0.025) than the other groups. There were significantly fewer reports of cardiotoxicity (p < 0.05) and severe intestinal toxicity (p < 0.02) in patients treated with the doxorubicin-DNA conjugate and there was a tendency towards less hepatic (p < 0.08) and renal toxicity (p < 0.08). The frequency of myelosuppression, fever and infectious complications was similar in all three groups. Complex binding to DNA appears to increase the therapeutic effects and reduce some toxic effects of doxorubicin in patients with ANLL.

Recombinant human leukocyte interferon modulates neutrophil function in vitro.

Recombinant human interferon-alpha 2 (rIFN-alpha A) was evaluated as a modulator of neutrophil functions. Neutrophils treated with rIFN-alpha A for 1 h in vitro showed reduced chemiluminescence (CL) and aggregation in response to phagocytosis. In contrast, when certain soluble stimuli [f-met-leu-phe (fMLP) or leukotriene B4] were used, rIFN-alpha A treatment conferred a doubling of CL. This was paralleled by a similar increase in superoxide anion production and a 56% increase of release of beta-glucuronidase and lysozyme. The NBT test showed that IFN treatment did not increase the number of responding neutrophils. However, there was a significant increase in the displaceable binding of fML[3H]P. Enzyme release, aggregation, and CL in response to other soluble stimuli, the ionophore A23187 and phorbol myristate acetate were unaffected by IFN treatment. Likewise, chemotaxis was not affected. Thus, phagocytosis-associated events and aggregation were hampered by rIFN-alpha A whereas secretory responses to receptor-dependent soluble stimuli were augmented. The mechanism for the latter is most likely dependent on the observed modulation of binding of fMLP to its receptor.

Therapeutic effects of low-dose cytosine arabinoside, alpha-interferon, 1 alpha-hydroxyvitamin D3 and retinoic acid in acute leukemia and myelodysplastic syndromes.

62 evaluable patients with myelodysplastic syndromes (MDS) or acute leukemia were treated with different combinations of low dose ara-C, alpha-interferon (IFN), 1 alpha-hydroxyvitamin D3 (vit D3) and retinoic acid. The aim was to study the efficacy and toxicity of each combination. The overall rate was 44%. Of these, 50% responded favorably to the combination of IFN, vit D3 and retinoic acid (IDR), which was comparable to the response rate of 43% for low-dose ara-C. The results of the IDR treatment may be explained by additive or synergistic effects between the separate drugs in the combination. Ara-C and IDR treatment was generally well-tolerated but interferon gave more side effects than any other drug used in the study. Evaluation of the full combination of ara-C, IFN, vit D3 and retinoic acid was not possible because of toxicity. Marrow hypoplasia was infrequent (5/27 patients) in cases responding favorably to treatment. Complete remissions were not longer than partial remissions or significant responses.

Relation to chemotactic factor gradients to neutrophil migration and orientation under agarose.

Chemotactic substances confer a migratory pattern for neutrophil granulocytes under agarose that is characteristic for each agent. To analyse the cause of such differences, we have studied neutrophil migration and orientation with f-Met-Leu-Phe (fMLP), leukotriene B4 (LTB4), and serum as chemoattractants. When these agents were used at optimal concentrations, it was observed that cells stimulated by LTB4 did not start migration as fast and did not migrate as far as those exposed to fMLP, but they maintained a higher degree of orientation. This delay in initiation of migration and maximal degree of orientation was even more marked when serum was the chemoattractant. These migration variables were related to the generation of gradients in the agarose of fML[3H]P, arachidonic-[3H]acid (AA, of which LTB4 is a metabolite), and fluorescein. The curvilinear AA gradient was flatter and more stable than those of fML[3H]P and fluorescein, which were linear. Thus, differences in the development and shape of the gradient of chemoattractant may contribute to differences in migration kinetics.

Effects of human interferon preparations on neutrophil function.

We have studied effects of two partially purified human leukocyte (alpha) interferon (IFN) preparations (PIF-A and PIF-B) and a highly purified fibroblast (beta) IFN on the functional activity of normal human neutrophils (PMNs). In vitro, PIF-B conferred a significant and dose-dependent enhancement of chemiluminescence (CL) induced both by phagocytosis and a soluble stimulus, f-Met-Leu-Phe, and decreased killing of Staph. aureus. In contrast, PIF-A caused only a slight inhibition of bactericidal activity and had no effects on CL. beta-IFN had no effects on either bactericidal activity or CL. Migration under agarose was decreased with all of the IFN but phagocytosis and release of enzymes was not affected. PMNs from seven patients treated with PIF-A for multiple myeloma exhibited increased CL responses but no other PMN functions were affected. The findings that human IFN preparations affect PMN functions indicate that high-dose IFN therapy of immunocompromised patients should be carefully evaluated for the possibility of increased infectious complications.

Leukotriene biosynthesis by polymorphonuclear leukocytes from two patients with chronic granulomatous disease.

Polymorphonuclear leukocytes (PMNL) isolated from two patients with chronic granulomatous disease (CGD) were tested for their ability to metabolize arachidonic acid to lipoxygenase products including 5(S),12(R)-dihydroxy-6,14-cis-8,10-trans-eicosatetraenoic acid (LTB4). Analyses of incubations of these PMNL with arachidonic acid and the calcium ionophore A23187 did not differ from simultaneous controls in the production of LTB4, other 5,12-dihydroxy-eicosatetraenoic acids, or monohydroxy-eicosatetraenoic acids. The clinical diagnosis of CGD was confirmed in both cases by determination of PMNL chemiluminescence. Leukocytes from both patients failed to generate active oxygen species in response to either LTB4 or formyl-methionyl-leucyl-phenylalanine. The observation of arachidonic acid oxidation in the absence of superoxide anion precludes a role for the active oxygen species in this metabolic process. These studies clearly dissociate the ionophore-induced leukocyte respiratory burst from the oxidation of arachidonate to the leukotrienes. In addition, the defect of CGD appears to be unrelated to the ability of PMNL to carry out arachidonate oxygenation.

Neutrophil functions and clinical performance after total fasting in patients with rheumatoid arthritis.

The effects of fasting for 7 days were investigated in 13 patients with rheumatoid arthritis (RA) in comparison with a control regimen in a cross-over trial. The effects of fasting on clinical performance and blood neutrophil functions were studied. During fasting, with a mean weight loss of 5.1 kg, clinical inflammation in the joints and the erythrocyte sedimentation rate (ESR) decreased. During the control period the joints either remained unchanged or deteriorated, and no change was observed in the body weight or the ESR. The locomotion of neutrophils under agarose, induced by a reference serum, decreased during the fasting period (p less than 0.001), but no change in their locomotion was induced by an Escherichia coli bacterial factor. During the control period, however, the locomotion induced by either stimulant was significantly decreased. Generation of migration-stimulating factors from the patients' plasma declined 3 days after the end of fasting (p less than 0.001). The adherence of the neutrophils to nylon fibres was unchanged during both periods. The bactericidal capacity improved during fasting, both in comparison with the initial value (p less than 0.005) and with the values from the control period (p less than 0.001). An association was found between improvement in inflammatory activity of the joints and enhancement of neutrophil bactericidal capacity. Fasting appears to improve the clinical status of patients with RA. This could partly be due to the observed changes in the functions of the neutrophils, since the latter contribute to the inflammatory joint reactions.

Effects of novel lipoxygenase products on migration of eosinophils and neutrophils in vitro.

Since it has been suggested that a lipoxygenase product might be specific chemotactic factor for eosinophils, we assessed the stimulating effects of a variety of lipoxygenase products (LTB4, 20-OH-LTB4, 20-COOH-LTB4 and 5(S)12(S)-DHETE) on both neutrophil and eosinophil migration under agarose. LTB4 was the most potent lipoxygenase cytotaxin for neutrophils as well as eosinophils and its stimulating potential for both cell types was similar. The other leukotrienes stimulated migration of neutrophils less than LTB4, whereas eosinophils did not respond. Thus, the previous suggestion that an eosinophil chemotactic factor could be identical with LTB4 was not verified.

Treatment of chronic lymphocytic leukaemia and well-differentiated lymphocytic lymphoma with continuous low- or intermittent high-dose prednimustine versus chlorambucil/prednisolone.

Prednimustine, a new antitumour drug, is a chlorambucil ester of prednisolone. The present prospective randomized study compares the effect of continuous low-dose (B) and intermittent high-dose (C) prednimustine in previously untreated patients with progressive CLL and WDLL. The control group received continuous chlorambucil/prednisolone therapy (A). One hundred and eighteen patients, 88 CLL and 30 WDLL, were evaluable. Response to therapy (greater than 50% improvement) was noted in 61, 55 and 57% in groups A, B and C respectively. The difference was not statistically significant. Time to response, response duration and survival did not show any differences between the groups. Responding patients survived longer than patients with stationary and progressive disease. Median survival time was 72 months from diagnosis and 52 months from start of therapy, with no differences between the treatment groups. Toxicity of prednimustine was usually mild and similar to that of the two constituents. Treatment schedule C showed a slight advantage with regard to frequency of side effects. In conclusion, in this study the therapeutic effect of prednimustine was equal to that of its constituents administrated separately.

A novel leukotriene produced by stimulation of leukocytes with formylmethionylleucylphenylalanine.

Stimulation of human polymorphonuclear leukocytes with the chemotactic peptide formylmethionylleucylphenylalanine led to the formation of a novel leukotriene: 5(S),12(R)-dihydroxy-6,8,10,14-eicosatetraen-1,20-dioic acid. This dihydroxydicarboxylic acid is derived from omega-oxidation of 5(S),12(R),dihydroxy-6,8,10,14-eicosatetradienoic acid (leukotriene B4). The intermediate 5(S),12(R),20-trihydroxy-6,8,10,14-eicosatetraenoic acid was also isolated from these incubations. The two metabolites of leukotriene B4 exhibit chemotactic properties for human polymorphonuclear leukocytes but are less active in this respect than the parent compound.