Randomized comparison of interferon α and hydroxyurea with hydroxyurea monotherapy in chronic myeloid leukemia (CML-study II):: prolongation of survival by the combination of interferon α and hydroxyurea

The optimum treatment conditions of interferon (IFN) alpha therapy in chronic myeloid leukemia (CML) are still controversial. To evaluate the role of hydroxyurea (HU) for the outcome of IFN therapy, we conducted a randomized trial to compare the combination of IFN and HU vs HU monotherapy (CML-study II). From February 1991 to December 1994, 376 patients with newly diagnosed CML in chronic phase were randomized. In all, 340 patients were Ph/BCR-ABL positive and evaluable. Randomization was unbalanced 1: 2 in favor of the combination therapy, since study conditions were identical to the previous CML-study I and it had been planned in advance to add the HU patients of study I (n = 194) to the HU control group. Therefore, a total of 534 patients were evaluable ( 226 patients with IFN/HU and 308 patients with HU). Analyses were according to intention-to-treat. Median observation time of nontransplanted living patients was 7.6 years (7.9 years for IFN/HU and 7.3 years for HU). The risk profile ( new CML score) was available for 532 patients: 200 patients (38%) were low, 239 patients (45%) intermediate, and 93 patients (17%) high risk. Complete hematologic response rates were higher in IFN/HU- treated patients ( 59 vs 32%). Of 169 evaluable IFN/HU- treated patients ( 75%), 104 patients (62%) achieved a cytogenetic response that was complete in 12% ( n = 21), major in 14% ( n = 24), and at least minimal in 35% ( n = 59). Of the 534 patients, 105 (20%) underwent allogeneic stem cell transplantation in first chronic phase. In the low-risk group, 65 of 200 patients were transplanted (33%), 30 (13%) in the intermediate-risk group, and nine (10%) in the high-risk group. Duration of chronic phase was 55 months for IFN/HU and 41 months for HU ( P<0.0001). Median survival was 64 months for IFN/HU and 53 months for HU-treated patients ( P = 0.0063). We conclude that IFN in combination with HU achieves a significant long-term survival advantage over HU monotherapy. In view of the data of CML-study I, these results suggest that IFN/HU is also superior to IFN alone. HU should be combined with IFN in IFN-based therapies and for comparisons with new therapies.