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In a randomized multicenter study the influence of hydroxyurea versus busulfan on the duration of the chronic phase and on survival of chronic myelogenous leukemia (CML) was determined. In addition cross resistance and adverse reactions of the drugs were analyzed. From July 1983 to January 1991, 441 CML patients were randomized to receive hydroxyurea or busulfan. Of these, 90.7% were Philadelphia positive; 25.7% were low, 38.2% intermediate, and 36.2% high risk patients according to Sokal's score. The median survival of the busulfan treated Philadelphia-positive patients is 45.4 months and of the hydroxyurea group 58.2 months (P = .008). The survival advantage for the hydroxyurea treated patients is recognized in all risk groups. Sixty four patients reached therapy resistance before blast crisis and were crossed over to the alternative drug. The 23 patients with primary hydroxyurea had a median survival of 5.6 years, the 41 patients with primary busulfan therapy a median survival of 2.7 years (P = .02). Adverse reactions were less frequent with hydroxyurea with no severe adverse effects (lung fibrosis, long lasting bone marrow aplasia). The analysis of white blood cell counts in the course of treatment showed lower counts in the hydroxyurea patients. We conclude that hydroxyurea is superior to busulfan in therapy of CML in chronic phase and should be used as first line therapy. Busulfan may have a role as secondary therapy after hydroxyurea resistance or intolerance.

Clinical aspects of 145 cases of nodular paragranuloma (nodular subtype of lymphocyte predominance type of Hodgkin's disease) were investigated. There was a marked male predominance, and the age curve showed a peak in the 4th decade. In a majority of cases lymphadenopathy developed within 1 year. General (B) symptoms were observed in only 15 patients. The most frequent sites of primary involvement were cervical, axillary, and inguinal lymph nodes. Other organs were rarely involved. At the time of diagnosis 50% of patients were in stage I, 21% in stage II, 22% in stage III, and 7% in stage IV. The prognosis was usually favorable or very favorable and depended on the stage of disease at diagnosis and on the age of the patient. Patients with stage I or III disease without splenic involvement had about the same probability of survival as the normal population. Stage III patients with splenic involvement had a lower probability of survival. The prognosis for stage II was also less favorable. Patients in stage IV had the lowest probability of survival. Closer analysis of the ten stage IV cases revealed two groups with different outcomes. Four cases showed progressive disease that did not respond to treatment and led to death within 12 months. The second, more favorable form (6 patients) responded well to chemotherapy. Nine patients in stage I who were not treated after lymph node biopsy were free of disease even after periods of up to 14 years. A total of 52 patients had one or more relapses. The recurrent tumors developed locally in a majority of cases. There was transformation of nodular paragranuloma into another subtype of Hodgkin's disease in only four cases. Five cases showed transformation into large-cell tumors that resembled immunoblastic lymphoma and require further immunological study.

From July 1983 to January 1991 a total of 622 patients were randomized (585 eligible) to compare the effects of hydroxyurea, interferon alpha (IFN), and busulfan on the duration of chronic phase, and survival. Further goals included the determination of prognostic parameters. 598 CML patients were documented and 575 evaluable. The Ph-status was known for 547 patients. 89.4% of the patients were Ph-positive (+). 11% had additional chromosome aberrations. The median survival of Ph+ patients by now is 4.2 years, that of Ph-patients 1.4 years. Ph-negative patients are older, tend to have lower cell counts and, as a group are more ill at diagnosis. A survival difference of about one year is expected between busulfan and hydroxyurea treated patients. Prospectively evaluated age, organomegaly related symptoms, Karnofsky index, extramedullary manifestations, number of erythroblasts and percent of circulating blasts proved to be of prognostic significance. A prognostic score (score 1) was determined which was superior to Sokal's score in the study population. 164 patients were randomized to receive IFN. In 54 patients (33%) IFN had to be terminated because of adverse effects, therapy resistance or other reasons. Clinically relevant neutralizing antibodies were detected in 9 cases. Most frequent adverse events were flu-like symptoms in 74%, gastrointestinal symptoms in 52%, and neurologic-psychiatric symptoms in 30% of patients. Reduction of the Ph-chromosome was observed in 13% of evaluable patients (10 of 75). In 4 patients complete cytogenetic remissions were observed, in three of these ongoing. Cytogenetic responders have a survival advantage. Interferon treated Philadelphia-negative CML patients have no survival disadvantage. The study is expected to allow statements as to the advantages or disadvantages of the use of busulfan, hydroxyurea and IFN in the treatment of CML as well as to the reliability of prognostic markers.