Gemtuzumab Ozogamicin Combined with Induction Chemotherapy in Young Adults with Acute Myeloid Leukemia: Review and Perspectives

Review Article

Ann Hematol Oncol. 2015; 2(7): 1055.

Gemtuzumab Ozogamicin Combined with Induction Chemotherapy in Young Adults with Acute Myeloid Leukemia: Review and Perspectives

Candoni A¹*, Fanin R¹ and Baccarani M²

¹Division of Hematology and SCT Unit, University of Udine, Italy

²Department of Hematology & Oncology, University of Bologna, Italy

*Corresponding author: Anna Candoni, Division of Hematology and Stem Cell Transplantation Unit, Santa Maria Misericordia University Hospital, University of Udine, 33100 Udine, Italy

Received: September 10, 2015; Accepted: November 20, 2015; Published: November 22, 2015

Abstract

Progress in treatment of acute myeloid leukemia (AML) is slow. Many new agents have been tested, but few were approved. Gemtuzumab Ozogamicin (GO) is a new AML-targeted drug that is composed by a monoclonal antibody targeting a surface antigen of myeloid leukemic cells (CD33) combined with a potent cytotoxic (calicheamicin). We review here the studies of GO in AML, including an update of the Italian studies, and we trace back the story of a drug that was developed 15 years ago and, regrettably, is no longer available for the treatment of AML, with the exception of Japan. GO was approved by the US FDA for the second-line treatment of AML in the elderly, and was shown by several European large prospective and randomized studies to be active also in first line, both alone, but particularly in combination with standard chemotherapy. Regrettably, a registration study that was performed in US could not confirm the superiority of GO and chemotherapy on chemotherapy alone, and the drug was withdrawn. The differences among the US and the European studies are discussed. The profile of the AML patients who are expected to benefit more by the reintroduction of GO is proposed: first-line, less than 60 years old, CD33 expressed in more than 20% leukemic cells, low/intermediate cytogenetic risk, and low expression of the PGP multidrug resistance protein.

Keywords: Acute myeloid leukemia; Gemtuzumab ozogamicin; Induction therapy; Multidrug resistance

Introduction

The therapy of many haematologic malignancies has improved dramatically in the last 30 years, but the therapy and the outcome of therapy of acute myeloid leukemia (AML) have changed only partially. Less than five new drugs have been approved for AML in the past 25 years (Gemtuzumab-ozogamicin, decitabine, azacitidine) [1,2].

Recent efforts to improve the efficacy of the therapy for remission induction have included several potential strategies such as modulation of anthracyclines and cytarabine doses, addition of multidrug resistance1 (MDR) modulators, and the use of targeted agents, sd Gemtuzumab-ozogamicin (GO) [1,3,4]. Particularly, GO has been investigated primarily as mono therapy (9 mg/sqm as a standard dose every 2 weeks) in elderly patients with relapsed disease, with a reported overall response rate (ORR) of 25-35%, and a median duration of response shorter than 8 months [5-9]. Based on these results, GO obtained approval, in May 2000, by the United States (US) Federal Drug Administration (FDA) for treatment of patients 60 years old, or older, with AML in first relapse who are not candidates for intensive cytotoxic therapy [9-11]. Then, the effectiveness of GO was also evaluated as first induction monotherapy, always in the elderly. More recently, some randomized trials with addition of GO to induction chemotherapy were performed confirming the potential role and the interest of GO in an induction setting [4-7,12-16].

Here, we review the studies testing GO for the induction of first remission in the specific setting of young adult patients with AML. In this context we also summarize the final results of a multicenter Italian trial where GO was combined with a FLAI scheme (fludarabine, cytarabine, and idarubicin) as induction strategy in AML patients less than 65 years old.

Gemtuzumab-Ozogamicin-Structure and Mechanism of Action

Gemtuzumab-ozogamicin (CMA-676; Mylotarg®) is a chemotherapy agent composed of a recombinant humanized anti- CD33 antibody (IgG4) conjugated with a cytotoxic antitumor antibiotic, calicheamicin, isolated from fermentation of a bacterium, Micromonospora echinospora ssp. Calichensis (Figure 1). The antibody portion of GO binds specifically to the CD33 antigen, a 67-kDA sialic acid-dependent adhesion protein expressed on the surface of leukemic blasts in more than 90% of AML but not on normal hematopoietic stem cells. The expression of CD33 peaks in promyelocytes and myelocytes, and is down regulated with maturation of myeloid lineage (mature granulocytes do not express CD33). The binding of the anti-CD33 antibody portion of GO with the CD33 antigen results in the formation of a complex that is rapidly internalized and transferred into lysosomes. Calicheamicin is then released with subsequent hydrolysis and binds in a sequence-specific manner the minor groove of DNA, resulting in DNA double strand breaks, cell cycle arrest and apoptosis.