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)

Iris Middeldorf, Oliver Galm, Rainhardt Osieka, Edgar Jost, James G. Herman, Stefan Wilop

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)477-481
Number of pages5
JournalAmerican Journal of Hematology
Volume85
Issue number7
DOIs
StatePublished - Jul 2010

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Acute Myeloid Leukemia
Methylation
Cytokines
Drug Therapy
Survival
CpG Islands
Therapeutics
gemtuzumab
Psychological Stress
Anti-Idiotypic Antibodies
Appointments and Schedules
Biomarkers
Monoclonal Antibodies
Morbidity
Polymerase Chain Reaction
Mortality

ASJC Scopus subject areas

  • Hematology

Cite this

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). / Middeldorf, Iris; Galm, Oliver; Osieka, Rainhardt; Jost, Edgar; Herman, James G.; Wilop, Stefan.

In: American Journal of Hematology, Vol. 85, No. 7, 07.2010, p. 477-481.

Research output: Contribution to journalArticle

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abstract = "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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