Human leukocyte interferon and intermittent high-dose melphalan-prednisone administration in the treatment of multiple myeloma: a randomized clinical trial from the Myeloma Group of Central Sweden.

In a randomized clinical trial intermittent high-dose melphalan/prednisone (MP) treatment has been compared with human leukocyte interferon (IFN) administration. Three to 6 X 10(6) IU of IFN was given im daily. Therapy was continued to progression of the disease. Fifty-five patients were randomized to receive MP and 75 were randomized to receive IFN. Forty-four percent of the patients receiving MP responded to therapy as opposed to only 14% of the patients receiving IFN (P less than 0.001). This difference was mainly due to a low response rate in IFN-treated IgG myelomas, while the response rate for IgA and Bence Jones myelomas did not differ significantly between the two treatment groups. Median duration of response was shorter for IFN-responding patients (23 months) as compared to patients in the MP group (35 months). During follow-up, second-line therapy was given more frequently in the IFN group (91%) than in the MP group (59%). Time on initial treatment was significantly shorter in the IFN group (3 months) than in the MP group (19 months). Since more patients responded to second-line therapy in the IFN group than in the MP group, total survival did not differ significantly between the two groups.

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.

A study of the reproducibility of the diagnostic criteria for acute leukaemia.

The Leukaemia Group of Middle Sweden recently started a new multicentre study of treatment of adult patients with acute leukaemia from 6 centres. The criteria for the diagnosis, subclassification, degree of leukaemic bone marrow infiltration, remission and relapse are to be used by the morphologists of 6 different pathology departments. The reproducibility of the criteria has been studied by 3 of the morphologists concerned, in a retrospective review of a strictly consecutive series of 79 adult patients treated at Södersjukhuset, Stockholm, Sweden, in the years 1978 to 1981. The results show that the reproducibility of the criteria and the concordance of the morphologists when using them increased when the criteria were made more detailed and precise.

Intermittent high-dose melphalan/prednisone vs continuous low-dose melphalan treatment in multiple myeloma.

Patients with newly diagnosed multiple myeloma were randomly allotted to an intermittent high-dose melphalan/prednisone (MP) treatment (120 patients) or a continuous low-dose melphalan (M) regimen (99 patients). The median observation time was 59 months (range 33-84). Response to therapy was obtained in 45% of the MP group and 31% of the M group (P less than 0.05). No significant difference in response with regard to clinical stage was noted. Median survival was 36 months in the MP group and 29 months in the M group. Survival was longer in stage I and II myeloma than in the stage III cases, at least in the MP group. The median and 5-yr survival rates in stages I and II were significantly better in the MP than in the M group. Response to therapy was associated with length of survival, median survival being 62 months in responding patients and 20 months in non-responders. The MP and M groups did not differ in this respect.

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.

Prednimustine and vincristine compared with cytosine arabinoside and thioguanine for treatment of elderly patients with acute nonlymphoblastic leukemia.

Sixty-seven patients with acute nonlymphoblastic leukemia (ANLL) and above the age of 60 years were randomly allocated to treatment with either prednimustine + vincristine or cycles with cytosine arabinoside and thioguanine. Of the 67 patients, 13 (19%) entered a complete remission and four a partial remission. Of 33 patients randomized to prednimustine and vincristine (15 adequately treated), three entered a complete remission and one a partial remission. Four further patients went into complete remission after a switch to other treatment modalities. Of 34 patients randomized to cycles of ARA-C and thioguanine (22 adequately treated), four entered a complete remission and three a partial remission with the correct program. One patient entered a remission with intermittent cytosine arabinoside + thioguanine (wrong program) and one further patient entered a complete remission after a switch to prednimustine and vincristine. Prednimustine + vincristine did not appear to be superior to treatment with cytosine arabinoside thioguanine cycles for elderly patients with ANLL.

Leukotriene B4 is a potent and stereospecific stimulator of neutrophil chemotaxis and adherence.

We studied the effects of leukotrienes on in vitro functions of neutrophil polymorphonuclear (PMN) granulocytes. Leukotriene B4 (LTB4) evoked a stimulated and directed migration of neutrophils under agarose with an optimum concentration of 10(-6)M, whereas two nonenzymatically formed isomers (compounds I and II) induced this response at 10(-5)M. Leukotriene C4 (LTC4) and 5-hydroxyeicosate-traenoic acid (5-HETE) did not affect this PMN migration. At the same optimum concentrations, LTB4 and compounds I and II augmented PMN adherence to nylon fibers. The chemotactic and adherence responses were of the same magnitude as with formal-Met-Leu-Phe (fMLP) at 10(-7)M. None of the leukotrienes influenced the spontaneous or phagocytosis-associated chemiluminescence or the ability to kill Staphylococcus aures. The cyclooxygenase inhibitor, indomethacin, inhibited only partly the fMLP-induced migration at high concentrations and stimulated migration at 2.5 x 10(-7)M, suggesting that arachidonic acid was then mainly metabolized by the lipoxygenase pathways. The lipoxygenase and cyclooxygenase inhibitor, eicosatetraynoic acid, inhibited both spontaneous and stimulated migration at greater or equal to 2.5 x 10(-5)M, but not at lower concentrations. Thus, since LTB4, and to a lesser degree compounds I and II, stimulated migration and adhesion, it is suggested that these mediators could be of importance for the emigration of neutrophils from blood vessels to areas of inflammation.

Comparison of daunorubicin and daunorubicin-DNA complex in the treatment of acute nonlymphoblastic leukemia.

Sixty consecutive patients, 15-60 years old, with ANLL were divided randomly into three groups for induction treatment with one of the following regimens: R1, daunorubicin (DNR) 1.5 mg/kg on day 1 + ARA-C 2 mg/kg body weight on days 1-5; R2, DNR 1.5 mg/kg on days 1 and 2 + ARA-C 2 mg/kg on days 4-8; R3, DNR-DNA complex 1.5 mg/kg on days 1 and 2 + ARA-C 2 mg/kg on days 4-8. Maintenance treatment consisted of monthly courses of DNR 1.5 mg/kg (R1, R2) or DNR-DNA 1.5 mg/kg (R3) combined with ARA-C 1 mg/kg on days 1-5, alternating with thioguanine 2 mg/kg PO on days 1-5 combined with ARA-C 1 mg/kg IV on days 1-5. Fourteen patients of 20 went into complete remission with R1, 13 or 18 with R2, and 15 of 22 with R3. The overall remission frequency was 70% and there was no significant difference between the different groups. The median time in first remission and the median survival time were 300 and 510 days, respectively, with R1; 335 and 495 days with R2; and 295 and 677 days with R3. There was no statistically significant difference between the groups treated according to the different regimens concerning the time in first remission. Survival was slightly better with R3 than with R1. Treatment with the DNR-DNA complex caused less pronounced thrombocytopenia and fewer 'minor' cardiac abnormalities than treatment with free DNR in the same dosage schedule.

Polymorphonuclear function in patients with skin and joint symptoms after small-intestinal shunt operations.

Previous studies have shown that the small-bowel shunt operation for morbid obesity may be followed by signs of enhanced cell-mediated immunity and polymorphonuclear (PMN) granulocyte bactericidal capacity. In the present study seven patients, operated 4 months--4.5 years previously and exhibiting postoperative arthralgias, arthritis, and/or skin rashes, were investigated with regard to their PMN adherence and bactericidal capacity and plasma levels of complement factors 3 and 4 (C3 and C4). There patients showed a decreased PMN bactericidal capacity compared both with 10 other shunt-operated patients without skin and joint symptoms and with healthy controls, whereas PMN adherence was lower than for the non-symptomatic patients but similar to that of the controls. Two patients had C3 levels above the reference value; all had normal C4 values. Thus, a small-bowel shunt operation for obesity, complicated by skin and joint symptoms, might be associated with decreased PMN bactericidal capacity.

Polymorphonuclear (PMN) function after small intestinal shunt operation for morbid obesity.

The possible influence on blood polymorphonuclear (PMN) granulocyte functions of the small intestinal shunt operation for obesity was studied in 10 massively overweight patients. They were investigated prior to operation and for 9 months afterwards, when they had lost an average of 32 kg body weight. Preoperatively they showed reduced PMN bactericidal capacity and increased PMN adherence compared with controls of normal weight. During the first 2--4 months postoperatively all patients displayed a gradually increasing bactericidal capacity, which then reached levels similar to the controls and remained so for the rest of the follow-up period. This enhancement was more easily assessed by a new in vitro assay in which each PMN was provided with 30--40 bacteria, than by a standard assay using 2--4 bacteria per granulocyte. PMN adherence decreased during the first postoperative months and then returned to preoperative levels. The changes in PMN functions were not statistically related either to each other or to the continuous loss of body wieght. Thus, impairment of PMN killing function occurring in extremely obese patients became normalized after small bowel shunt operation, while the high adherence remained unchanged.

Activation of the bactericidal capacity of blood granulocytes. Evaluation of a new method and the effect of levamisole.

In most polymorphonuclear (PMN) bactericidal assays each PMN is given appr. 0.5-4 bacteria to kill but it has not been sufficiently shown that this ratio is optimal for the detection of changes in PMN killing functions. One PMN, incubated with increasing amounts of Staph. aureus, can kill between 45 and 90 colony forming units (CFU). Therefore a new assay, giving each PMN a submaximal bacterial amount (i.e. using 2-4 CFU/PMN) concerning the effects on PMNs of thermal inactivation and of levamisole. Exposure to 46 degrees C for 3-5 minutes decreased the killing capacity, easiest descernable with the standard assay. Incubation with levamisole in concentrations ranging between 10(-6) and 10(-7) mol/l increased the PMN killing capacity, and this was most evident with the modified assay. Thus, enhancements of PMN killing functions might be detected better with the present modified PMN bacterial assay, whereas impairments are disclosed more readily with the standard assay.

Treatment of acute nonlymphoblastic leukemia in adults with daunorubicin-DNA complex: a preliminary report.

Forty-four adult patients under 60 years of age with acute nonlymphoblastic leukemia were randomized for induction treatment with one of the following three regimens: R 1 = courses of daunorubicin on day 1 + ARA-C on days 1--5; R 2 = courses of daunorubicin on days 1 and 2 + ARA-C on days 4--8; R 3 = courses of daunorubicin-DNA complex on days 1--2 + ARA-C on days 4--8. Out of 14 patients, 9 went into remission on R 1, 6 out of 14 on R 2, and 8 out of 16 on R 3. The preliminary results suggest that daunorubicin-DNA complex has the same efficacy for inducing remission as daunorubicin alone, if the same time intervals and dosages are used.

Oxymetholone treatment in myelofibrosis.

In order to study the effect of oxymetholone therapy in advanced myelofibrosis, 11 patients (4 females, 7 males) were given, 3--5 mg per kg body weight, long-term oxymetholone treatment in a prospective multicenter study. Five cases had previously had a diagnosis of polycythemia vera. All patients had anemia initially, 4 leukocytopenia and 10 thrombocytopenia in addition. Hepato-splenomegaly was present in all cases but in varying degree. Five patients required regular blood transfusions before treatment. In 9 of the 15 courses given, there was normalization of the peripheral blood or substantial improvement (better than 3 g hemoglobin/dl or 50 X 10(9) platelets/1) after androgens. Significant effects were noted both on hemoglobin values and platelet counts. The need for blood transfusions ceased completely in all 5 cases. When oxymetholone treatment was reduced or interrupted 4 patients relapsed; 2 of them responded to a renewed course. The red cell counts returned to previous polycythemic values in one patient and another died from acute leukemia. The results of this study suggest that androgens might be of value in advanced cases of myelofibrosis with transfusion-requiring anemia or severe thrombocytopenia.