Decitabine and Gemtuzumab Ozogamicin in Acute Myelogenous Leukemia and High-Risk Myelodysplastic Syndrome

Gemtuzumab ozogamicin (GO) is a humanized monoclonal antibody directed against the CD33 epitope linked to calicheamicin. Concomitant use of hypomethylating agent (HMA) can potentially open up the chromatin structure and make it more accessible to calicheamicin. Alternately HMAs can increase expression of tumor suppressor Syk (inactivated by hypermethylation), which docks to intracellular tail of CD33 upon its ligation by anti-CD33 antibody. We report on a phase 2 study of GO with decitabine (DAC) in patients with acute myelogenous leukemia (AML) and high-risk myelodysplastic syndrome (MDS).

Patients were eligible if they belonged to one of 4 groups; Group1: relapsed/refractory AML with remission duration (CRD) < 1 year, Group 2: relapsed/refractory AML with CRD ≥ 1 year, Group 3: untreated AML/MDS not candidates for intensive chemotherapy and Group 4: patients treated for MDS evolving to AML. All patients had adequate performance status (ECOG ≤ 3) and organ function. Treatment regimen included Decitabine 20mg/m2 daily for 5 days and GO 3 mg/m2 on day 5. If day 14 bone marrow aspirate had > 5% blasts patients received additional Decitabine 20 mg/m2 IV on day 15. Patients with response or stable disease could get up to 5 post-induction cycles of therapy with DAC+GO (without day 15 DAC) and responding patients could continue with single agent DAC every 4 – 6 weeks beyond post-induction therapy up to a total of 24 cycles of therapy.

A total of 110 were enrolled including 81 patients with AML (74%) and with 29 high-risk MDS (26%); Group 1= 28 (25%), Group 2=5 (5%), Group 3= 57 (52%), Group 4= 20(18%). Median age was 70 years (range, 27–89) and 63 (57%) were males. Median ECOG PS was 1 (range, 0 – 3). Median white cell count, hemoglobin, platelet count and bone marrow (BM) blast percentage at diagnosis were 2.5 × 10⁹/l (range, 0.3 – 121.9), 9.3 g/l (range, 6.9 – 31.9), 37 × 10⁹/l (range, 3 – 816), and 32% (range, 0 – 96), respectively. FLT3 mutations were identified in 12 (13%) of 95 evaluated patients. 45 (41%) patients had high-risk cytogenetic features.

Complete remission (CR/CRi) was achieved in 39 (35%) of 110 evaluable patients; Group 1= 5/28 (17%), Group 2 = 3/5 (60%), Group 3 = 24/57 (42%), and Group 4 = 7/20 (35%) (Table 1). Patients received a median of 2 (1 – 23) treatment cycles with the median number of cycles to response among those who responded being 2 (1 – 5). Median duration of CR/CRi was 5.8 (range, 1 – 41) months. The most common study drug-related adverse events were hemorrhage/bleeding, gastrointestinal toxicities including nausea and mucositis and cardiac related issues in 10%, 7%, and 4% of patients; respectively. Grade 3 and 4 toxicities were note in 16 (14.5%) patients. Neutropenic fever requiring hospitalization occurred in 59 of 110 treated patients (49%) with 7 of these being documented as fungal infection.

Combination of GO and Decitabine is effective and well tolerated particularly in patients with less heavily pre-treated AML/high-risk MDS and not eligible for intensive induction regimens.

Off Label Use: Use of decitabine, 5-azacytidine, SAH, and valproic acid in the treatment of older patients with AML. Kantarjian:Genzyme: Research Funding. Burger:Pharmacyclics: Consultancy, Research Funding. Verstovsek:Incyte Corporation: Research Funding; Novartis: Research Funding; AstraZeneca: Research Funding; Celgene: Research Funding; SBIO: Research Funding; Lilly Oncology: Research Funding; Bristol-Myers: Research Funding; Geron Corp.: Research Funding; Gilead: Research Funding; YM Biosciences: Research Funding; Roche: Research Funding; NS Pharma: Research Funding; Infinity Pharmaceuticals: Research Funding. Faderl:Genzyme: Membership on an entity's Board of Directors or advisory committees, Research Funding. Cortes:Pfizer: Research Funding. Borthakur:Easia: Research Funding.