Hydroxyurea, azacitidine and gemtuzumab ozogamicin therapy in patients with previously untreated non-M3 acute myeloid leukemia and high-risk myelodysplastic syndromes in the elderly: results from a pilot trial

Abstract

Elderly patients with acute myeloid leukemia (AML) and high-risk myelodysplastic syndromes (MDS) have a poor prognosis due to low response rates (26-46%) to standard chemotherapy and high treatment-related mortality (11-31%). In this Phase II study, we used a combination of hydroxyurea (HU), azacitidine and low dose gemtuzumab ozogamicin (GO) to assess its efficacy and toxicity in this group of patients. Twenty patients with non-M3 AML and MDS were treated with this regimen. The treatment was begun with HU 1500 mg orally twice daily to lower white blood cell count below 10,000/microL, followed by azacitidine 75 mg/m(2) subcutaneously for 7 days and GO 3 mg/m(2) on day 8. Patients who achieved complete remission (CR) received a consolidation course. The median age of patients was 76 years. Eleven patients (55%) were treated in the outpatient setting. Fourteen (70%) achieved a CR, three of which were incomplete (CRi). The median duration of remission was 8 months and median survival was 10 months. Performance status of 0-1 was associated with high complete response rate. Overall toxicity was acceptable with only one (5%) early death due to disease progression. The combination of HU, azacitdine and GO appears to be a safe and effective regimen in the treatment of AML and high risk MDS in the elderly. These results need to be confirmed in a larger cohort of patients.

Acute myeloid leukaemia in the elderly: a review

“…A randomized Phase III study of standard induction with or without GO in younger patients was terminated early for a lack of benefit and increased toxicity, leading to the FDA's request that it no longer be commercially available. However, GO could be beneficial in the elderly population in a variety of scenarios: as part of consolidation or maintenance therapy; with cytarabine (Piccaluga et al, 2004;Fianchi et al, 2008) or immunotherapy; with lower intensity therapies like azacitidine; (Nand et al, 2008) administered using a fractionated dosing regimen; (Taksin et al, 2007) or accompanying autologous transplantation (Cascavilla et al, 2008).…”

Sequence of administration and methylation of SOCS3 may govern response to gemtuzumab ozogamicin in combination with conventional chemotherapy in patients with refractory or relapsed acute myelogenous leukemia (AML)

“…VOD, a severe complication with thrombosis of small liver veins, was reported with an incidence of 7-20% in studies using GO before chemotherapy [8,29,32,37]. However, in studies using GO after chemotherapy, incidence of VOD seems to be lower [22,33,36]. In our patient cohort, mainly including patients who received chemotherapy first followed by GO, no VOD was observed.…”

“…During myelosuppression, in almost all patients (88%) neutropenic fever emerged and four patients (17%) subsequently died due to infectious complications. Treatment-related mortality was reported to be 5-13% in published studies using GO after chemotherapy [22,33,36], whereas mortality in studies using GO before chemotherapy seemed to be higher (19-57%) [8,11,37,43]. Of note, multiple responses were observed in a single patient treated repeatedly with GO.…”

“…Chemotherapy followed by GO resulted in 10-70% CR and a median OS of 2.3 to 11 months [22,[33][34][35][36]. Doses of GO ranged from 3 to 9 mg/m 2 [25,37].…”

Gemtuzumab ozogamicin in combination with vorinostat and azacitidine in older patients with relapsed or refractory acute myeloid leukemia: a phase I/II study

“…6 Likewise, DNA methyltransferase I inhibitors such as azacitidine or decitabine have been demonstrated to enhance GO efficacy in vitro, 7,8 possibly through lowering of the apoptotic threshold, and early clinical studies have indicated activity in patients with AML. [9][10][11] These studies, together with the improved clinical activity reported when HDAC inhibitors are used with DNA methyltransferase I inhibitors, 12 prompted a phase I/II study with vorinostat and azacitidine as chemosensitizers for GO in the treatment of primary refractory AML or AML in first relapse (remission duration ≤12 months) requiring first salvage therapy. Epigenetic therapeutics such as the histone deacetylase inhibitor, vorinostat, and the DNA methyltransferase I inhibitor, azacitidine, enhance gemtuzumab ozogamicin efficacy in vitro.…”