Randomized, parallel-group comparison of interferon alfa-2b plus hydroxyurea versus hydroxyurea alone in patients with chronic myelogenous leukaemia in chronic phase

A STUDY was undertaken to compare the effect of recombinant interferon alfa-2b (IFN alfa-2b) plus hydroxyurea (HU) with that of HU alone on haematological remission (HR) in patients with chronic phase chronic myelogenous leukaemia (CML). Twenty-one patients were randomized to receive either IFN alfa-2b plus HU (n = 12; seven male and five female; mean age 40 years, range 29–57 years) or HU alone (n = 9; three male and six female; mean age 35 years, range 24–50 years). All patients initially received cytoreductive therapy with HU alone, at a dose according to the white blood cell (WBC) count. When the WBC count decreased to 5−10 × 10³/μl, patients were randomized to receive either IFN alfa-2b 2 million units per day by subcutaneous (s.c.) injection plus the adjusted daily dose of HU (> 150 × 10³/μl, 4g; 50−150 × 10³/μl, 3g; 30−50 × 10³/μl, 2g; 10−30 × 10³/μl, 1g; and 5−10 × 10³/μl, 0g), or HU alone. Thus, patients received no HU until their WBC count rose above 5−10 × 10³/μl. Eleven of 12 patients on IFN plus HU achieved a haematological response, including nine with complete haematological remission (CHR) (A1: n = 0, A2: n = 4, A3: n = 3, A4: n = 2) and two with partial haematological remission (PHR) (B1: n = 0, B2: n = 2), while none of the nine patients on HU alone achieved a remission with the above-mentioned doses of HU according to our criteria (A[CHR]: WBC count maintained below 9 × 10³/μl without blast and no symptoms or signs associated with CML; subclassified according to the percentage of Ph¹ chromosome: A1, Ph¹ chromosome present in all analyzable metaphases; A2, Ph¹ chromosome present in 35–59%; A3, 5–34%; A4, Ph¹ chromosome absent from all analyzable metaphases. B[PHR]: B1, reduction of peripheral WBC count by at least 50% to < 20 × 10³/μl; B2, normalization of peripheral WBC count but persistence of immature form or clinically palpable splenomegaly. Failure: patients who failed to achieve a PHR or CHR as defined above). Using two sets of primer pair sequences encoding bcr-abl mRNA (A primer: 5′-GGAGCTGCAGATGCTGACCAAC-3′ encoding bcr exon II; B primer: 5′-TCAGACCCTGAGGCTCAAAGTC-3′ encoding abl exon II; A′ primer: 5′-CCTGATCTCCTCTGA CTATGAG-3′ encoding bcr exon I; B′ primer: 5′-TCCAGCGAGAAGGTTTTCCTTG-3′ encoding abl exon I), we performed the cDNA-PCR analysis, which revealed persistent bcr-abl mRNA expression in the peripheral mononuclear cells from two patients who achieved CHR induced by IFN. We suggest that IFN therapy should be continued at least until molecular remission is achieved.