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)

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 5 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 5 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. Am. J. Hematol. 85:477-481, 2010. V

What Happened to Anti-CD33 Therapy for Acute Myeloid Leukemia?

“…The optimal timing of treatment with GO combined with chemotherapy remains unclear. In the same retrospective study, response rate and OS were significantly higher in patients receiving chemotherapy before GO than in patients receiving GO before chemotherapy or GO alone [40].…”

“…As personalized therapeutic approaches based on molecular characterization of disease become routine, CD33-directed therapies may play a more prominent role in the treatment of defined subpopulations of AML patients. Identification of biomarkers predictive of response may also inform treatment decisions, allowing these constructs to be used more effectively [40].…”

“…There was a trend towards a higher response rate (86% vs 56%) and longer median OS (25.1 vs 10.3 months) in patients with SOCS3 hypermethylation compared with unmethylated SOCS3. This study suggests that methylation status of SOCS3 may serve as a biomarker in predicting response to anti-CD33-directed therapy and warrants prospective evaluation [40]. The optimal timing of treatment with GO combined with chemotherapy remains unclear.…”

Retrospective Analysis of Clinical Factors Relating to the Outcome of Gemtuzumab Ozogamicin Therapy

“…The combination of GO with other antileukemic agents is known to improve the response to GO therapy 2 . Additionally, the administration of GO a few days after conventional chemotherapy appears to provide improved response and survival as compared to GO monotherapy 20 . Further clinical trials with large sample groups are necessary to establish the ef cacy of GO and to determine the group of patients most likely to bene t from GO therapy.…”

Methylation and microRNA-mediated epigenetic regulation of SOCS3

“…Twenty out of 51 patients with prostate cancer were detected for hypermethylation of SOCS3 [54]. Hypermethylation of SOCS3 was observed in 8 out of 24 patients diagnosed with acute myelogenous leukemia [55]. CD33 receptor was identified as a myeloid specific marker and SOCS3 was reported to inhibit CD33 receptor mediated cell proliferation.…”