What Led to U.S FDA’s Re-Approval of Mylotarg

On September01, 2017, the United States Food and Drug Administration (US FDA) approved gemtuzumab ozogamicin (Brand Name – Mylotarg®, manufactured by Pfizer) for the treatment of newly diagnosed CD33-positive acute myeloid leukaemia (AML– a type of blood cancer)in adult patients,and as a new treatment for CD33-positive AML that is either relapsed (went into remission, then came back) or refractory (did not go into remission with other leukaemia treatments) in adults and in paediatric patients aged 2 years and older. It is the first therapy indicated for pediatric patients with AML.

Overview of AML:

AML is a rapidly progressing cancer of the bone marrow and blood, in which high number of abnormal myeloblasts (a type of immature/abnormal white blood cells [WBCs]) are produced. Sometimes, a high number of abnormal red blood cells and platelets are produced in AML. These abnormal cells hinder the production and functioning of normal blood cells. According to the U.S. National Cancer Institute, more than 21,000 patients will be diagnosed with AML, and approximately 10,600 patients will succumb to it in2017. Data from 2005-2014 reveals that the rate of new AML cases has been rising at an average of 3.1% each year.AML is a relatively rare disease and is more common in older adults and among men. AML is the second most common leukemia in children affecting around 500 children every year. Survival duration of 5 years or more is reported only in about 25% of AML patients.

Mylotarg –Mechanism of Action:

Mylotargis an antibody-drug conjugate (ADC) composed of the cytotoxic agent calicheamicin, attached to a monoclonal antibody targeting CD33(an antigen expressed on the surface of myeloblasts in about 90% of AML patients). When ADC binds to the CD33 antigen on the tumour cell surface, it is absorbed into the cell and calicheamicin is released. The free calicheamicin induces double-strand DNA breaks, subsequently inducing cell cycle arrest and apoptotic cell death.

Clinical Trial Results That Led to Approval:

Mylotarg was initially approved in year 2000 at a higher dose under the FDA’s accelerated approval program for use as a single agent in patients with CD33-positive AML, aged 60 years or older, who had experienced a relapse. In year 2010, Mylotarg was voluntarily withdrawn from the U.S. after subsequent confirmatory trials failed to verify clinical benefit, and there was a higher rate of fatal toxicity compared to chemotherapy. Current approval includes a lower recommended dose, a different schedule as a combination with chemotherapy or as a single agent, and a new patient population.

Current approval was based on the efficacy and safety results from various clinical trials including ALFA-0701, AML-19, and MyloFrance-1.

Common side effects observed with Mylotarg include fever, nausea, infection, vomiting, bleeding, low levels of platelets in the blood, swelling and sores in the mouth, constipation, rash, headache, elevated liver function tests, and low levels of certain WBCs. Severe side effects of Mylotarg include low blood counts, infections, liver damage, and haemorrhage. In addition, the boxed warning for Mylotarg says that it can cause severe or fatal liver damage in some patients.

What Experts Say about Mylotarg:

Dr Richard Pazdur, director of FDA’s Oncology Centre of Excellence, said”We are approving Mylotarg after a careful review of the new dosing regimen, which has shown that the benefits of this treatment outweigh the risk. Mylotarg’s history underscores the importance of examining alternative dosing, scheduling, and administration of therapies for patients with cancer, especially in those who may be most vulnerable to the side effects of treatment”. Liz Barrett, global president of Pfizer Oncology, said “The FDA approval of Mylotarg fills a critical unmet need for many adults and children with AML, which can be fatal in a matter of months or even weeks if not treated and has a high relapse rate.

Scope of Mylotarg in India:

According to a study, in India, the biggest constraint is the cost of treatment and the absence of a health security to treat patients with AML.Fortunately, the mortality rate of leukaemia in India is less than that in western countries. The average mortality rate of leukaemia in India has decreased by 4.6% since 1990 and is 0.2% a year, currently. It is expected that a single cycle of Mylotarg will costs around $24,600.Considering the high cost of newly approved treatment and the other options currently available for treatment of AML, it can be assumed that this drug will hardly be of any use in India, in near future.

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