TY - JOUR
T1 - 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)
AU - Middeldorf, Iris
AU - Galm, Oliver
AU - Osieka, Rainhardt
AU - Jost, Edgar
AU - Herman, James G.
AU - Wilop, Stefan
PY - 2010/7
Y1 - 2010/7
N2 - In older patients suffering from acute myelogenous leukemia (AML), aggressive chemotherapy is accompanied with high treatment-related morbidity and mortality. Gemtuzumab ozogamicin (GO), a humanized monoclonal anti-CD33 antibody, represents a well tolerated treatment option, but optimal treatment schedules are still unknown. Additionally, Suppressor of cytokine signaling 3 (SOCS3) inhibits the CD33-induced block on cytokine-induced proliferation. Consequently, a variable response of AML cells to anti-CD33-targeted therapy may be caused by modulation of SOCS3 expression. Twenty-four patients with refractory or relapsed CD33-positive AML received GO as a single agent before or after conventional chemotherapy. The methylation status of the SOCS3 CpG island was assessed by methylation-specific polymerase chain reaction. Response (RR) and overall survival (OS) were significantly higher in 16 patients receiving chemotherapy before GO (RR 81%, OS 14.8 months) compared to three patients who received GO single agent therapy (RR 33%, OS 7.2 months) or 16 with GO before chemotherapy (RR 0% OS 2.2 months, P = 0.01 for RR and P <0.001 for OS). Methylation of the SOCS3 CpG island was found in 8/24 patients. There was a trend towards a higher RR and longer OS in patients with SOCS3 hypermethylation (RR 86%, OS 25.1 months) compared to unmethylated SOCS3 (RR 56%, OS 10.3 months, P = 0.09). Administration of GO a few days after chemotherapy seems to provide better response and survival compared to administration of GO directly before chemotherapy. The potential role of SOCS3 hypermethylation as a biomarker should be further investigated in patients undergoing GO containing therapies.
AB - In older patients suffering from acute myelogenous leukemia (AML), aggressive chemotherapy is accompanied with high treatment-related morbidity and mortality. Gemtuzumab ozogamicin (GO), a humanized monoclonal anti-CD33 antibody, represents a well tolerated treatment option, but optimal treatment schedules are still unknown. Additionally, Suppressor of cytokine signaling 3 (SOCS3) inhibits the CD33-induced block on cytokine-induced proliferation. Consequently, a variable response of AML cells to anti-CD33-targeted therapy may be caused by modulation of SOCS3 expression. Twenty-four patients with refractory or relapsed CD33-positive AML received GO as a single agent before or after conventional chemotherapy. The methylation status of the SOCS3 CpG island was assessed by methylation-specific polymerase chain reaction. Response (RR) and overall survival (OS) were significantly higher in 16 patients receiving chemotherapy before GO (RR 81%, OS 14.8 months) compared to three patients who received GO single agent therapy (RR 33%, OS 7.2 months) or 16 with GO before chemotherapy (RR 0% OS 2.2 months, P = 0.01 for RR and P <0.001 for OS). Methylation of the SOCS3 CpG island was found in 8/24 patients. There was a trend towards a higher RR and longer OS in patients with SOCS3 hypermethylation (RR 86%, OS 25.1 months) compared to unmethylated SOCS3 (RR 56%, OS 10.3 months, P = 0.09). Administration of GO a few days after chemotherapy seems to provide better response and survival compared to administration of GO directly before chemotherapy. The potential role of SOCS3 hypermethylation as a biomarker should be further investigated in patients undergoing GO containing therapies.
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U2 - 10.1002/ajh.21723
DO - 10.1002/ajh.21723
M3 - Article
C2 - 20575043
AN - SCOPUS:77954900623
SN - 0361-8609
VL - 85
SP - 477
EP - 481
JO - American Journal of Hematology
JF - American Journal of Hematology
IS - 7
ER -