Phase 1 study of polyethylene glycol formulation of interferon alpha-2B (Schering 54031) in Philadelphia chromosome-positive chronic myelogenous leukemia.
Interferon alpha (IFN-alpha) therapy improves prognosis in Philadelphia chromosome (Ph)-positive chronic myelogenous leukemia (CML). Polyethylene glycol (PEG) attached to IFN-alpha prolongs its half-life and may offer better therapy. The aims of this phase 1 study were to define the maximal tolerated dose (MTD), dose-limiting toxicities (DLTs), and response with PEG IFN-alpha-2b. Twenty-seven adults with Ph(+) CML in chronic or accelerated phases, in whom IFN-alpha treatment had failed, were studied. Patients had hematologic (9 patients) or cytogenetic resistance (12 patients) or intolerance to IFN-alpha (6 patients). PEG IFN-alpha-2b was given as a weekly subcutaneous injection starting at 0.75 microg/kg weekly and escalating to 1.5, 3, 4.5, 6, 7.5, and 9.0 microg/kg. The MTD was defined at 7.5 to 9 microg/kg; DLT included severe fatigue, neurotoxicity, liver function abnormalities, and myelosuppression. Longer administration of PEG IFN-alpha-2b resulted in chronic side effects not observed earlier, which defined the MTD and DLT. The proposed phase 2 dose of PEG IFN-alpha-2b was 6 microg/kg weekly. Among 19 patients with active disease, 7 (37%) achieved complete hematologic response (CHR); 2 (11%) had a cytogenetic response (complete). Among 8 patients treated in CHR, 7 (87%) improved cytogenetic response to complete (4 patients) or partial (3 patients). All 6 patients intolerant to IFN-alpha tolerated PEG IFN-alpha-2b; 4 improved their cytogenetic response. The results show that PEG IFN-alpha-2b is easier to deliver (once weekly), better tolerated, and perhaps more effective than IFN-alpha.
Talpaz
M
M
Department of Bioimmunotherapy, M. D. Anderson Cancer Center, Houston, TX, USA.
O'Brien
S
S
Rose
E
E
Gupta
S
S
Shan
J
J
Cortes
J
J
Giles
F J
FJ
Faderl
S
S
Kantarjian
H M
HM
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D002626:Chemistry, Pharmaceutical; D020732:Cytogenetic Analysis; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000188:drug therapy* / Q000235:genetics* / Q000378:metabolism; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D010677:Philadelphia Chromosome; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D011994:Recombinant Proteins
D000970:Antineoplastic Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D011092:Polyethylene Glycols