CD33 Expression and Gentuzumab Ozogamicin in Acute Myeloid Leukemia: Two Sides of the Same Coin

Acute myeloid leukemia (AML), the most frequent acute leukemia in adults, has been historically treated with infusional cytarabine (ara-c) + daunorubicin (3 + 7) for at least 40 years. The first “target therapy” to be introduced was the monoclonal anti-CD33 gemtuzumab ozogamicin (GO) in 2004. Unfortunately, in 2010 it was voluntarily withdrawn from the market both for safety reasons related to potential liver toxicity and veno-occlusive disease (VOD) and because clinical studies failed to confirm the clinical benefit during induction and maintenance. Seven years later, GO was re-approved based on new data, including insights into its mechanism of action on its target receptor CD33 expressed on myeloid cells. The present review focuses on current biological information and clinical data from several studies investigating GO. Cytogenetic, molecular, and immunophenotypic data are now able to predict the potential positive advantages of GO, with the exception of high-risk AML patients who do not seem to benefit. GO can be considered a ‘repurposed drug’ that could be beneficial for some patients with AML, mostly in combination with new drugs already approved or currently in testing.

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Target Therapy in Acute Myeloid Leukemia

10.5772/intechopen.94422 ◽

2020 ◽

Author(s):

Vasko Graklanov

Keyword(s):

Clinical Trials ◽

Acute Myeloid Leukemia ◽

Elderly Patients ◽

Acute Leukemia ◽

Mechanism Of Action ◽

Myeloid Leukemia ◽

Target Therapy ◽

New Drugs ◽

Cytotoxic Treatment ◽

Acute Myeloid

Acute myeloid leukemia (AML) is the most common form of acute leukemia in elderly patients. Over the past four decades the basic therapeutic armamentarium was the standard cytotoxic treatment. The new insights in understanding the pathogenesis of AML was the momentum that revolutionized the treatment landscape in AML. The last five years unprecedented growth has been seen in the number of target therapy drugs for the treatment of AML. These new drugs did not just have a clinical benefit as single agents but also have improved AML patient outcomes if combined with conventional cytotoxic therapy. Here, we review recent advances in target-based therapy for patients with AML focusing on their mechanism of action and the results from already published clinical trials.

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Acute myeloid leukemia transformed to a targetable disease

Future Oncology ◽

10.2217/fon-2019-0670 ◽

2020 ◽

Vol 16 (14) ◽

pp. 961-972

Author(s):

Khalil Saleh ◽

Nadine Khalifeh-Saleh ◽

Hampig Raphael Kourie

Keyword(s):

Acute Myeloid Leukemia ◽

Stem Cell ◽

Stem Cell Transplantation ◽

Myeloid Leukemia ◽

Gemtuzumab Ozogamicin ◽

Mechanisms Of Action ◽

New Drugs ◽

Traditional Treatment ◽

Heterogeneous Neoplasm ◽

Acute Myeloid

Acute myeloid leukemia (AML) is a heterogeneous neoplasm characterized by the monoclonal proliferation of immature progenitors. It is the most common acute leukemia in adults and its incidence increases with age. The standard traditional treatment in fit patients was the ‘3 + 7’ regimen and cytarabine consolidation followed or not with allogeneic stem cell transplantation. Recently, several targeted therapies such as gemtuzumab ozogamicin targeting the CD33+ AML, midostaurin, gilteritinib and crenolanib inhibiting FLT3-positive AML and ivosidenib and enasidenib blocking IDH-mutated AML have been approved. These new drugs led to the change of the landscape of the treatment of AML and transforming this disease to a targetable one. We aimed in this paper to review the implications of each new target, the mechanisms of action of these new drugs and we discuss all the studies leading to the approval of these new drugs in their indications according to each target.

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Gemtuzumab ozogamicin in acute myeloid leukemia: a remarkable saga about an active drug

Blood ◽

10.1182/blood-2013-03-490482 ◽

2013 ◽

Vol 121 (24) ◽

pp. 4838-4841 ◽

Cited By ~ 100

Author(s):

Jacob M. Rowe ◽

Bob Löwenberg

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Phase 1 ◽

Randomized Study ◽

Gemtuzumab Ozogamicin ◽

New Drugs ◽

Phase 2 ◽

Newly Diagnosed ◽

Phase 3 ◽

Acute Myeloid

Abstract Despite living in an era of unprecedented progress in the understanding of the genetic and molecular biology of acute myeloid leukemia (AML), this has not translated into significant advances in therapy. Never before have so many potential targets been studied. Yet most have not advanced beyond the phase 1 and, occasionally, phase 2 studies. The few ongoing phase 3 studies seem unlikely to have more than a marginal benefit, if at all. Thus, it is not surprising that in past few decades almost no new drugs for AML have received regulatory approval. In 2000, gemtuzumab ozogamicin (GO) was granted accelerated approval by the US Food and Drug Administration based on promising phase 2 data in relapsed older adults with AML. GO held promise as a new agent that also could be efficacious in newly diagnosed AML with acceptable toxicity. Several phase 3 studies were designed to test GO in this setting. The results of a randomized study by the Southwest Oncology Group led in 2010 to the voluntary withdrawal of this agent when improved efficacy could not be demonstrated and toxicity appeared excessive. Since then, 4 randomized studies have been completed that, in aggregate, strongly support the efficacy of this agent in newly diagnosed AML with acceptable toxicity. There is a very plausible explanation for this discrepancy, making a compelling case for reapproval of GO in AML.

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