Background: Hypomethylating agents are approved for the treatment of myelodysplastic syndrome (MDS) and have activity in acute myelogenous leukemia (AML) (

Issa, JP et al.
Blood
.
2004
;
103
:
1635
–40
)(
Silverman LR et al.
Journal of Clinical Oncology
2006
;
24
:
3895
–3903
). Exposure of AML cells to hypomethylating agents increase their CD33 expression (
Balain and Ball.
Leukemia
.
2006
;
20
:
2093
–2101
). This establishes a rationale for the combination of hypomethylating agent with CD33 antibody for treatment of high-risk MDS and AML. A preliminary report of the combination of 5-azacitidine (Aza) and gemtuzumab ozogamicin (GO) in elderly patients with previously untreated AML and MDS showed promise (
Nand, S. et al.
Blood
2006
;
108
:
Abstract 1981
).

Patients and Method: We have started enrolling patients in a phase 2 study of Decitabine (DAC) with GO in patients with AML and high-risk myelodysplastic syndrome (MDS). Treatment includes DAC 20 mg/m2/day intravenously (IV) × 5 days and GO 3 mg/m2 IV on day 5. GO is repeated on day 15±2 of first cycle if peripheral blood blast count is > 109/L. Six such cycles are planned every 4–8 weeks. Patients achieving clinically relevant response e.g. complete remission (CR), CR with incomplete platelet recovery (CRp), marrow clearance/reduction of blasts etc. can continue on DAC alone approximately every 4–8 weeks for up to 24 cycles of total therapy duration. Based on historical expectations patients are divided into four groups according to study design:

  1. relapsed AML 1st CR duration <= 1 year or beyond first relapse,

  2. relapsed AML 1st CR duration > 1 year,

  3. untreated AML (not eligible for standard induction)/MDS,

  4. previously treated MDS, secondary MDS or AML.

Results: Thirty-seven patients have been treated till date; Group 1=19, group 2=1, Group 3=12 and group 4=5. Median age is 63.5 years (range, 26–82), performance status =1 (range, 0–3), prior therapy =1 (range, 0–7). Eighteen (49%) patients has adverse cytogenetics and 14 (38%) has prior malignancies. Two patients received day 15±2 administration of GO. Median number of treatment cycles is 2 (range, 1–5). Eight patients died while on study. Except for cytopenias, infections, infusion related reactions etc. no significant grade 3/4 toxicities have been encountered. Three patients have achieved CR/CRp and 5 patients achieved other clinically relevant responses with an overall response rate of 22%. Responses according to patient groups are; Group 1=2/19 (4 ongoing), group 2=1/1, group 3=2/12 (3 ongoing), group 4=3/5. Seven additional patients are continuing on study with stable disease. Accrual to the study is ongoing.

Conclusion: The combination of DAC and GO appears promising particularly in less heavily pre-treated patients with high-risk MDS and AML.

Topics:
decitabine, gemtuzumab, leukemia, myelocytic, acute, myelodysplastic syndrome, cd33 antigen, c-reactive protein, cyclic amp receptor protein, epley maneuver, antibodies, azacitidine

Disclosures: No relevant conflicts of interest to declare.

Author notes

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2008, The American Society of Hematology
2008
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