The German CML Study, Comparison of Busulfan vs. Hydroxyurea vs. Interferon alpha and Establishment of Prognostic Score 1

Abstract

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.

Effectiveness and cost-effectiveness of imatinib for first-line treatment of chronic myeloid leukaemia in chronic phase: a systematic review and economic analysis

“…Two studies described the methods of randomisation 6,81 and the other two studies failed to provide details of randomisation.…”

“…21 Length of follow-up was not stated in the Broustet trial (1991) 6 and was 3 years after the last patient was randomised in the study by Hehlmann and colleagues (1994). 81 Patient characteristics and treatment details are presented in more detail in Appendix 7.…”

“…Hehlmann and colleagues 81 state that randomisation lists were computed according to Elfron and stratified for participating hospitals. Suitable patients were randomised by telephone from a central location.…”

“…Clinical data on survival, HR and CR were obtained from studies by Hehlmann and colleagues, 81 The Italian Cooperative Study Group on CML, 89 Ozer and colleagues 90 and Kantarjian and colleagues. 91 Utilities were assessed by a clinical panel, and were 0.9 for patients receiving IFN-␣ therapy, 1.0 for patients receiving HU therapy and 0.5 for patients in the blast or accelerated phase.…”

Interferon alfa as primary treatment of chronic myeloid leukemia: long-term follow-up of 71 patients observed in a single center

“…Four of the five patients without ongoing cytogenetic remission were off IFN at the time of followup. Given the dubious prognosis of patients discontinuing IFN, 12 some further decline in the proportion of surviving patients may be expected to occur with longer follow-up. The majority of long-term surviving patients, however, have achieved and maintained complete cytogenetic remission.…”