A Phase II Trial of Combination Therapy with Arsenic Trioxide (ATO) and Gemtuzumab Ozogamicin (GO) in Patients with High-Risk Myelodysplastic Syndromes (MDS) or Acute Myeloid Leukemia (AML) Arising from MDS.

Background: Bone marrow findings in high-risk MDS are similar to those found in AML. MDS-associated myeloblasts are just as likely to express CD33 as AML myeloblasts, and cytogenetic abnormalities are similar to those of older AML patients (pts). Therapies effective in AML may also have activity in advanced MDS. GO is an anti-CD33 monoclonal antibody covalently linked to calicheamicin, a cytotoxic agent. ATO works through apoptotic and pro-differentiating mechanisms, and may allow for enhanced GO cytotoxicity. Methods: We conducted a multicenter trial in pts with high-risk MDS (IPSS score >1.5, or FAB or WHO classification with >5% CD33+ myeloblasts) or AML arising from MDS (with CD33+ myeloblasts) who had not received previous induction therapy, from 2/04 – 6/06. Pts received ATO (0.25mg/kg IV d1–5 during week 1, then twice weekly weeks 2–12) and GO (3mg/m 2 on day 8) for 1 or 2 12-week cycles. Pts who had stable disease or improvement on a week 12 bone marrow biopsy received a second 12-week cycle, and then another week 24 biopsy. The primary endpoint was response as defined by the Modified International Working Group (IWG) criteria for MDS or, for AML patients, the IWG response criteria for AML. Results: Twenty-two pts have been enrolled; 21 are evaluable for response. The median age was 69 years. Fourteen pts (64%) had MDS (4 RAEB-1, 8 RAEB-2, 2 CMML-2,) with IPSS cytogenetic risk groups of good (2), intermediate (6), poor (4) and no growth (2), and IPSS classifications of high (5), Int-2 (5), and Int-1 (2). Eight pts (36%) had AML with cytogenetic risk groups as defined by CALGB 8461: intermediate (4), adverse (3), and unknown (1). Fifteen pts received prior therapies, including growth factors (10), 5-azacytidine (5), hydroxyurea (3), prednisone (1), anagrelide (1), thalidomide (1), and lenalidomide (1). Pts had a median of 15% blasts: 11.5% for MDS pts; 43.5% for AML pts. Of the 21 pts, 11 (52%) completed 1 cycle of therapy; an additional 5 (24%) completed 2 cycles. Reasons for discontinuing therapy included: withdrawing consent (5), progressive disease (7), and toxicity (4). Responses occurred in 8 patients (38%): 8 (38%) by the IWG MDS criteria; 2 of 8 AML pts (25%) by the IWG AML criteria; and 2 (9%) by both criteria. Using the modified IWG MDS criteria, 2 patients had a partial remission, 3 had a neutrophil response, 2 had a platelet response, and 1 had both platelet and neutrophil response. Using the IWG AML Criteria, 2 AML pts achieved a partial remission. Grade3/4 non-hematologic toxicities included neutropenic fever or infection (6), fatigue (4), pulmonary complications (3), hepatotoxicity (1), renal failure (1), prolonged QTc (1), nausea (1), epistaxis (1), hypoxia (1). Of 20 pts evaluable for 6 month survival, 15 (75%) were alive, 7 (47%) of whom responded to treatment. Of 12 patients evaluable for 1-year survival, 4 (33%) were alive, 2 of whom responded to treatment. Pts who completed two cycles of therapy spent a median of 13 days in the hospital. Conclusion: The combination of ATO + GO is well-tolerated and yields hematologic responses, particularly in neutrophils and platelets. This combination may be a viable alternative to high-dose, inpatient therapy in pts with high-risk MDS or secondary AML.