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

Abstract

The optimum treatment conditions of interferon (IFN) a 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 CMLstudy I and it had been planned in advance to add the HU patients of study I (n ¼ 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 ¼ 21), major in 14% (n ¼ 24), and at least minimal in 35% (n ¼ 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 (Po0.0001). Median survival was 64 months for IFN/HU and 53 months for HU-treated patients (P ¼ 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.

Gender aspects in chronic myeloid leukemia: long-term results from randomized studies

“…20,21 The recruited patients represent about 10% of CML patients in Germany (West-Germany until 1990) during the recruitment period. In both trials inclusion criteria were newly diagnosed chronic phase CML, no prior therapy and treatment requirement as defined by the presence of at least one of the following criteria: unexplained fatigue, weight loss of more than 10% body weight in 6 months, fever exceeding 38.51C on five consecutive days, organomegaly-related symptoms, WBC count of more than 50 Â 10 9 /l or platelet count of more than 1 Â 10 12 /l at the time of recruitment.…”

“…18 Differences in gender-specific incidence and prognosis have long been recognized also in chronic myeloid leukemia (CML). 19 Male predominance was demonstrated in clinical trials, 20,21 and the Sokal score for younger patients (o45 years old) has identified female sex as a favorable prognostic factor. 22 These findings, however, never have been followed up systematically, and gender-associated differences have not been studied well in CML.…”

“…22 These findings, however, never have been followed up systematically, and gender-associated differences have not been studied well in CML. We therefore used 856 well-characterized patients from the German CML-studies I and II 20,21 to analyze possible gender differences in signs, symptoms, and prognostic factors at diagnosis, remission variables, duration of chronic phase and survival according to treatment in a systematic fashion.…”

Factors influencing adherence in CML and ways to improvement: Results of a patient-driven survey of 2546 patients in 63 countries

“…The 10-year survival probability increased from 20 to 53% with previous usually interferon alpha (IFN)-based standard therapy (Hehlmann et al 2003(Hehlmann et al , 2007 to about 90% in the imatinib era (Bjorkholm et al 2011;Hehlmann et al 2011). Given the treatment success and approximately 6000 newly diagnosed patients per year in Europe (Hoffmann et al 2015) and 6600 in the US (Howlader et al 2015) maximizing adherence to promote optimal outcomes is crucial.…”

The German competence network ‘Acute and chronic leukemias’

“…[12][13][14] The prolongation of survival achieved over the years for the various leukemias by the study groups forming the network are depicted in Figure 3-5. [15][16][17][18] The orientation of the network towards innovation and success makes the network attractive for new participants. The cooperation within the network and the thereby accomplished synergy yield an added value for all network partners.…”