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The pharmacokinetics of E. coli derived recombinant human interleukin-3 (rhIL-3) was studied following intravenous (i.v.) and subcutaneous (s.c.) bolus injection of rhIL-3. After i.v. bolus injection in eight patients, serum peak levels of 34.5-135.0 ng/ml were reached, followed by a rapid decline with a t1/2 alpha of 17 +/- 2 min and a t1/2 beta of 59 +/- 7 min. After s.c. bolus injection in five patients, the absorption was more prolonged with peak serum levels reached at 2.8 +/- 0.4 h. Elimination was also more protracted, and serum base-line levels were reached at 14-24 h. The immediate effect of rhIL-3 on peripheral white blood cells was less pronounced and more variable than previously found for G- or GM-CSF. Following i.v. administration, neutrophils showed a moderate drop to median 64% of initial values (range 42-85%) at median 30 min after injection (range 15-60 min) followed by an increase at 24 h to 69-288% of initial values. Eosinophils dropped to a median nadir of 34% and then gradually increased to maximum values in the range 135-720% at 18-24 h. The effect of rhIL-3 was further examined following i.v. injection of autologous 111Indium-labelled granulocytes in six patients. In steady state, i.v. injection of rhIL-3 caused a moderate drop in 111Indium activity of peripheral blood within 20 min without tendency to subsequent recovery. No change occurred in the activity recorded over the lungs and liver. The activity over the spleen decreased moderately in two patients. These results are strikingly different from those previously obtained after i.v. injection of rhGM-CSF.

The diagnostic value of abdominal ultrasound and lymphography was compared in the staging of 88 consecutive patients with malignant lymphoma, examined during the period March 1990 to April 1991. Lymphography was used as the reference method in the evaluation of the paraaortic and iliac lymphnodes. In 19% of the patients ultrasound examination could not be accomplished optimally, and these results were evaluated in a separate group. Lymphography demonstrated involvement of retroperitoneal lymphnodes in 27 patients, among these ultrasound was false negative in seven (= 26%). In ten patients ultrasound examination demonstrated lymphoma outside the lymphographic area. No false positive ultrasound examinations were found in the group with negative lymphography. Ultrasound cannot replace lymphography, but is an important supplement, and in those cases where ultrasound reveals lymphomas in the lymphographic area, lymphography can be omitted as ultrasound has a high predictive value.

Pharmacokinetics of recombinant human non-glycosylated bacterially-synthesized (E. coli) granulocyte-macrophage colony-stimulating factor (GM-CSF) were studied following single intravenous (i.v.) and subcutaneous (s.c.) bolus injection, and compared to equivalent doses of glycosylated mammalian-derived CHO-GM-CSF. Each route of administration gave a different GM-CSF concentration-time profile. The highest peak serum concentrations (Cmax) were observed following i.v. bolus injection. After i.v. administration, a two-phase decline in concentration was noted for both types of GM-CSF with a significantly shorter t1/2 alpha of 7.8 minutes for the E. coli GM-CSF versus 20.0 min for the CHO-GM-CSF, while no significant difference was observed for the terminal phase. Following s.c. administration of equivalent doses, a higher peak serum concentration was observed in the E. coli-treated patients and, again, a faster elimination where pretreatment serum levels were reached after 16-20 h, versus more than 48 h after administration of CHO-GM-CSF. Although the non-glycosylated E. coli GM-CSF thus seems to undergo a faster elimination that the glycosylated CHO-GM-CSF no significant difference could be demonstrated in the in vivo effect of corresponding doses of the two compounds with respect to stimulation of granulopoiesis--with reservation for small patient numbers and a large individual variations in response.

The malignant haematological disorders comprise the main groups leukemia, malignant lymphoma and multiple myeloma and the potentially malignant disorders: myelodysplastic syndrome, polycythaemia vera, myelofibrosis and M-component of uncertain significance. The common feature of all these disorders is monoclonality, i.e. they originate from one single cell. Around 2,000 new cases are diagnosed per year in Denmark. Because of the relative small number of patients, complex diagnosis and treatment (especially the possibility of cure on intensive treatment) a high degree of centralization is warranted to secure an evenly distributed high level of patient care and research. The present rules for referral of patients are unsatisfactory. A new referral system is proposed based on a common set of rules, agreed upon by five haematological centers in Denmark and the surrounding region, comprising diagnostic procedures, treatment, research and development for all haematological patients in the area. Based on these common rules (functional centralization) it is decided whether the individual patient can be treated in the primary hospital or should be referred to a center (geographical centralization). Recommendations about diagnosis, treatment and referral are made in this report. Detailed suggestions are given for diseases which may be treated locally whereas no detailed regimens are given for diseases and disease stages which should be centralized. In the latter cases, the main emphasis is placed on a presentation of treatment results.

This paper presents an overview of four Cancer and Leukemia Group B studies in 1266 patients with stage III-IV non-Hodgkin's lymphoma. The cases were analyzed across protocols; the major prognostic determinants were prior chemotherapy, age, and histology. The four studies proved that cyclophosphamide maintenance was superior to no maintenance even after prolonged intensive induction chemotherapy. Furthermore, the reinforcement program of monthly pulse doses of vincristine and prednisone, whose value was established in the treatment of acute leukemia, led to highly significant improvement in remission duration and survival. Other facets of the chemotherapy programs are still being subjected to analysis, but this report sets out some preliminary conclusions.

In a randomized, prospective trial from 1974-1978, 73 patients with non-Hodgkin's lymphomas in clinical Stage I or II were treated with extended field radiotherapy alone (RT) or RT plus adjuvant chemotherapy with vincristine, streptonigrin, cyclophosphamide and prednisone (RT + CT). With a median follow-up time of five years, 54% have relapsed in the RT group versus only 10% in the RT + CT group (P less than 0.01). There is no statistical difference in the overall survival yet, but 13/14 deaths in the RT group versus only 3/12 in the RT + CT group were due to progressive disease. Among patients with unfavorable histology, 13/22 in the RT group have died from disease progression against 3/34 in the RT + CT group (P less than 0.01). The results are in agreement with those from two other series published in detail. Based on these results we therefore recommend to use adjuvant CT with RT in all Stage I-II patients with unfavorable histology. Further observation is necessary before a conclusion can be drawn for the lymphoma patients with more favorable histology.

134 bacteraemic episodes in 112 patients with leukaemia and allied disorders over a 5-year period were reviewed. The patients were divided, with respect to neoplastic disease, into 3 prognostic groups according to estimated periods of survival of years (group 1), months (group II) or weeks (group III). High mortality was correlated to group III, gram-negative rod bacteraemia and septic shock. Low leucocyte levels and intensive antineoplastic treatment did not adversely influence the prognosis of the bacteraemic patients. Appropriate antibiotic therapy was correlated with a significantly lower mortality, and it is concluded that aggressive antibiotic therapy is indicated when bacteraemia is suspected from clinical judgement.

In an ongoing cooperative study of the Cancer and Acute Leukemia Group B, 21 evaluable patients with advanced malignant lymphomas were treated with 70 mg/m2 of cis-dichlorodiammineplatinum(II) (cis-platinum) once every 3 weeks. All patients had received extensive prior therapy. Partial remission was obtained in two of seven patients with Hodgkin's disease, for 1+ and 7 months, and in three of 14 patients with non-Hodgkin's lymphoma, for 2, 2+, and 2.5 months. In another ongoing trial, 11 patients with advanced, pretreated small cell cancer of the lung received 80 mg/m2 of cis-platinum once every 3 weeks. Four patients achieved partial remissions. These lasted 2+ and 2.5 months in the two patients evaluable for duration of response. Two further clear-cut tumor regressions were noted. The major toxic effects were myelosuppression and vomiting. In the second trial, one case of probable drug-related fatal nephrotoxicity was encountered despite optimal forced diuresis with mannitol and furosemide. cis-Platinum definitely warrants further evaluation in these diseases because of significant effectiveness even after extensive prior treatment.

The occurrence of malignant lymphomas in 3 siblings is described. The cases include the first report of Hodgkin's disease and non-Hodgkin malignant lymphoma in dizygotic twins. Another remarkable feature was the development of malignant lymphoma, when the siblings were at the same age. Although a transmissible agent or environmental factors cannot be excluded in this family, our observations may suggest a mutual genetic predisposition in Hodgkin's disease and non-Hodgkin malignant lymphoma.

VP-16-213 has been used in 5-day courses together with cyclophosphamide, doxorubicin (Adriamycin), vincristine, and prednisone for treatment of 74 consecutive patients with non-Hodgkin's lymphomas. Ninety-one percent of patients with favourable histology and 69% with unfavorable histology achieved complete or partial remissions (overall response rate of 76%). The frequency of complete remission was disappointingly low (22%), possibly due to reduction of doses of the other myelosuppressive agents in the present combination. Further trials with VP-16-213 in other combination chemotherapy are required.

In a cooperative study of the Cancer and Acute Leukemia Group B, 27 evaluable patients with advanced malignant lymphomas were treated with 70 mg/m2 of cisdichlorodiammineplatinum(II) (cis-platinum) once every three weeks. All patients had received extensive prior therapy. Partial remission was obtained in two of eight patients (25%) with Hodgkin's disease, for six and 40 weeks, and in five of 19 (26%) patients with non-Hodgkin's lymphoma, for a median duration of six weeks. The major toxic effects were profuse vomiting and, to a lesser degree, myelosuppression. Nephrotoxicity was easily controlled. Cis-platinum is an active agent in lymphoma and should merit incorporation into combination therapy for recently diagnosed disease.

Rubidazone, a semisynthetic daunorubicin derivative, was administered to 33 patients with advanced solid tumors or malignant lymphomas. The doses used were 200, 150, or 100 mg/m2 repeated at 3-week intervals. The antitumor effect was very modest. Partial remission was obtained in only one patient and stable disease was observed for periods of 4--18 weeks in seven additional patients. The major toxic effects were gastrointestinal and myelosuppressive. In two patients, cardiac toxic effects were noted and one patient had an anaphylactic-like reaction. No clinical cross-resistance seemed to exist between rubidazone and adriamycin.

Six hundred fifty-eight cases of previously untreated non-Hodgkin's lymphoma seen between 1970 and 1979 at the Medical Department, the Finsen Institute, were the basis for a comparative study of the prognostic value of the Rappaport, Kiel, and Lukes & Collins classifications and the new translation system, the Working Formulation of Non-Hodgkin's Lymphoma. Each histopathologic system proved equally effective in separating patients into subgroups with a spectrum of prognoses ranging from a median survival of less than 1 year to greater than 7 years. The established classifications were compared with the Working Formulation in order to evaluate its translational value. The Working Formulation was more similar to the Rappaport and the Lukes & Collins systems than to the Kiel system, since 82%, 89%, and 75% of the cases, respectively, were translatable following the guidelines outlined in the National Cancer Institute (NCI)-sponsored study. Similarities among the four systems were demonstrated in lymphomas with follicular growth pattern, and in diffuse lymphomas composed of small mature appearing lymphocytes or small cleaved lymphocytes. Incongruity among the systems was more marked in lymphomas composed of large lymphoid cells or in lymphomas of mixed cellular composition. A comparison was performed for each classification against the Working Formulation. All such subdivided subsets were tested for prognostic heterogeneity and the following conclusions were reached: the diffuse poorly differentiated lymphocytic category of Rappaport was separated into two subgroups (malignant lymphoma [ML] small cleaved cell and ML lymphoblastic) with different prognoses (P = 0.01); the diffuse "histiocytic" lymphomas were prognostically homogeneous, since none of the newer systems were able to identify subpopulations with significantly different prognoses; the subtypes of the Kiel classification were prognostically homogeneous; the only weakness of the Lukes & Collins classification was the undefined cell subtype, encompassing two populations with different prognoses; and (5) the importance of follicular growth pattern was confirmed for small cleaved cell and mixed cell cytology, whereas large cell cytology implied a poor prognosis regardless of pattern. By the use of the Cox regression model it could be demonstrated that the Working Formulation can substitute any of the established classifications in terms of prognostic value.

A prospective, randomized trial comparing treatment of 61 febrile episodes with cefotaxime (CTX) versus a combination of ampicillin, methicillin, and netilmicin (AMN) was carried out in 58 patients with leukaemia or malignant lymphoma, of whom 28 had a granulocyte count of less than or equal to 500 X 10(6)/l. The overall response frequency was 63% for CTX against 49% for the AMN combination, the latter figure being lower than generally reported in the literature. The difference was not statistically significant. In 21 episodes pathogens were isolated, 16 of them from the blood. All isolated bacteria but one, a strain of Bacteroides fragilis, were fully sensitive to at least one of the three antibiotics in the combination, and all but one, a strain of Listeria monocytogenes, were fully sensitive to CTX. These results indicate that CTX seems to be a promising alternative as monotherapy for empiric treatment of febrile episodes in patients with haematologic malignancies. Further investigations will, however, be required before completely rational choices between mono and combination therapy of febrile episodes in immunosuppressed patients can be made.

Meningeal involvement (MI) by non-Hodgkin's lymphoma (NHL) was seen in 38/602 patients (6.3%). In relation to histologic subtype the frequency of MI was: Follicular small cleaved and mixed cell 2/128 (1.6%), small lymphocytic and diffuse small cleaved cell 2/83 (2.4%), large cell and immunoblastic 13/295 (4.5%), small noncleaved cell 6/31 (19%), lymphoblastic 15/66 (23%). Risk factors that predict for MI were, besides histologic subtype, age under 40 yr, clinical stage IV, site of involvement (bone marrow, bone, skin gastrointestinal tract), and a poor response to initial therapy. In a Cox multivariate model encompassing the intermediate and high grade malignancy groups of the Working Formulation (WF), the 3 most important risk factors were histology, age, and stage. The estimated 1-yr probability of MI for combinations of the 3 risk factors was: 3 risk factors (61%), 2 risk factors (15-28%), 1 risk factor (4-8%), 0 risk factor (1.5%). At the diagnosis of MI, 84% of the patients had evidence of advanced systemic NHL, and the median survival after MI was 10 wk. CNS prophylaxis with whole-brain irradiation and intrathecal chemotherapy can only be recommended in patients with 2 or 3 risk factors. Improvement of the systemic chemotherapy might be the most important factor for prevention of MI in NHL.

Prednimustine, a chlorambucil ester of prednisolone, was administered to 16 patients with non-Hodgkin lymphomata (NHL) and 14 patients with chronic lymphocytic leukaemia (CLL), all previously treated with steroids and alkylating agents. Response was obtained in 8 patients with NHL and 11 patients with CLL. Two NHL patients had long-lasting complete remissions. Median duration of response for lymphomata was 12 weeks, for CLL more than 15 weeks. Delayed reversible and rather pronounced myelosuppression was the major side-effect observed in median 6 weeks from the start of Prednimustine with a median duration of 4 weeks.

A consecutive series of 21 previously untreated patients with low-grade non-Hodgkin lymphomas were treated with mitoxantrone 5 mg/m2 daily for 3 days every 3 weeks. The cumulative dose did not exceed 165 mg/m2 in any patient. In this group, 7 patients had small lymphocytic lymphomas, 10 patients had follicular small cleaved cell lymphomas, and 4 patients had follicular mixed small- and large-cell lymphomas. Of the 21 patients, 20 obtained remission (complete in 6, partial in 14), and 15 of these are still in remission. Relapse-free survival is 68% at 2 years. None of the patients has died. Nonhematologic toxicity was modest. No severe alopecia was seen, and only 6 patients had nausea and vomiting (WHO grade 1-3). No cardiac toxicity was seen. In conclusion, mitoxantrone is a highly active and well-tolerated drug in this subset of patients. Hematologic toxicity, especially leukopenia, was dose limiting, and a reduction of the dose was necessary in 15 out of the 21 patients.

Thyroid function was studied in 36 patients with various stages of malignant lymphoma. Stage IVB patients exhibited characteristic changes in thyroid biochemistry in the form of lowered triiodothyronine (T3) and elevated free thyroxine (FT4), but normal thyroxine. Moreover, the concentration of thyroxine-binding prealbumin and albumin was lowered, whereas thyroxine-binding globulin was normal. Thyroid-stimulating hormone was slightly elevated but showed a normal increase after administration of thyrotrophin-releasing hormone. Patients with less extensive disease differed only slightly from the controls. The results agree with previous studies of patients suffering from other chronic diseases. The mechanisms underlying the hormonal changes have been only partially elucidated. When investigating patients with disseminated malignant disease for thyroid disease, the above mentioned changes in thyroid biochemistry must be borne in mind. Single analyses of FT4 and T3 may give rise to a false assumption of hyper- or hypothyroid states in patients who are in fact euthyroid.

Of 315 patients from Scandinavia and West Germany with cutaneous T cell lymphoma, thirty-six (11.4%) had specific antibodies reactive against human T cell lymphotropic virus type I (HTLV-I). Among the HTLV-I antibody-positive patients, one had Sézary syndrome; five, mycosis fungoides, plaque stage; sixteen, mycosis fungoides, plaque stage with nondiagnostic histologic features; and three, lymphomatoid papulosis. All the patients from the Copenhagen area had several samples taken during the course of their disease, but the HTLV-I antibody titer was unaltered independent of the clinical stage the individual patient had at the time of the study. Eighty-three patients with non-Hodgkin's lymphoma were tested for HTLV-I antibodies, and all except two showed negative results. The finding of specific antibodies reactive against HTLV-I in cutaneous T cell lymphoma suggests that a retrovirus related to HTLV-I plays an important role in the pathogenesis of cutaneous T cell lymphoma.

29 patients with advanced malignant lymphoma were included in a phase-II trial conducted by Cancer and Acute Leukemia Group B. The patients received cis-diamminedichloroplatinum (DDP) in a dose of 70 mg/m2 every three weeks. In this still ongoing study, 23 patients are already evaluable. Out of 23 cases partial remission was observed in 6. The main toxicity was profuse vomiting. Myelosuppression and nephrotoxicity were both manageable. Based on these preliminary data, the incorporation of DDP in combination chemotherapy for malignant lymphoma appears to be warranted.

Of 602 patients treated for non-Hodgkin's lymphomas, 9 developed overt acute nonlymphocytic leukemia or preleukemia with refractory cytopenia and cytogenetic abnormalities of the bone marrow. A Kaplan-Meier estimate of the cumulative probability of leukemic complications was 6.3 +/- 2.6% (mean +/- SE) 7 years after start of treatment. All 9 patients with leukemic complications belong to a major subgroup of 498 patients treated with alkylating agents, predominantly cyclophosphamide. The risk of leukemic complications in this subgroup was compared with the risk in 312 patients treated with other alkylating agents for Hodgkin's disease, and with the risk in 553 patients treated with dihydroxybusulfan for ovarian carcinoma. Cumulative 9-year risks were 8.0 +/- 3.3%, 12.8 +/- 3.5%, and 7.1 +/- 1.9%, respectively. The general risk of secondary leukemia after long-term treatment with alkylating agents ranges from 1% to 1.5% per year from 2 to at least 9 years after start of treatment.