In this interview, Alan S. Gamis, MD, MPH, speaks with i3 Health about the recent FDA approval of gemtuzumab ozogamicin (MylotargTM, Wyeth Pharmaceuticals, LLC) for pediatric patients aged 1 month and older with newly diagnosed CD33-positive acute myeloid leukemia (AML). Dr. Gamis, lead investigator of the phase 3 Children's Oncology Group Trial AAML0531, which provided the basis for the approval, discusses the significance of the approval and shares his advice for health care providers as they begin prescribing gemtuzumab ozogamicin for their patients.
What are some of the most challenging aspects of treating pediatric and young adult patients with newly diagnosed CD33-positive AML?
Alan S. Gamis, MD, MPH: Despite the progress in survival with the incorporation of gemtuzumab ozogamicin, AML continues to be one of the most difficult childhood cancers to cure, with overall survival rates far below the average cure rates of childhood cancers overall. Therapy for AML in children is extremely intensive and fraught with severe acute complications, and it poses substantial risk for long-term sequelae in those who are cured. Additionally, AML is a very heterogenous cancer with many acquired genetic mutations ultimately leading to AML development. This creates great difficulty in finding a simple approach that will effectively benefit all patients with AML.
Can you comment on the significance of the approval of gemtuzumab ozogamicin in this patient population?
Dr. Gamis: Gemtuzumab ozogamicin is, surprisingly, the first agent specifically approved for the treatment of newly diagnosed AML in children. Our other therapeutics are approved in adults, but not specifically in children. Due to the ubiquitous presence of this agent's target—CD33—in most AML cells, it has broad applicability for childhood AML. It is an immunotherapeutic or conjugated antibody that attempts to avoid the severe toxicity seen with the traditional high-dose chemotherapy commonly used in AML. There is a great need to find alternative approaches, because we as a profession have reached a ceiling in the intensity with which drugs can be safely administered in fighting AML. Gemtuzumab ozogamicin is one of the first to surpass that ceiling safely.
How do you foresee the treatment of pediatric and young adult patients with newly diagnosed CD33-positive AML evolving in the coming years?
Dr. Gamis: The broad use of gemtuzumab ozogamicin will hopefully lead to greater relapse-free survival in these patients—this is the primary benefit seen in trials to date. With further research, we hope to more accurately predict who will benefit from this agent's use and who will not, thus being able to utilize it more wisely. The approval of gemtuzumab ozogamicin validates and strengthens an immunologic approach to AML therapy from which future therapies can build.
Do you have any words of advice for community oncologists and hematologists treating pediatric and young adult patients with gemtuzumab ozogamicin?
Dr. Gamis: While gemtuzumab ozogamicin is a step towards improved care, it needs to be used wisely. In AAML0531, we utilized it early in therapy, on the day after the last anthracycline treatment was given. Our data suggests that this is a safe and effective approach to its administration. We identified that later use of it, given as a second overall dose during intensification, was associated with toxicity. Thus, while it has not been studied or validated via a randomized trial, we would only give a single dose or set of doses—such as seen in the ALFA-0701 trial—during the first course of induction. We now consider it a standard of care. Further studies are underway to assess whether the degree of CD33 expression on the leukemic cell truly correlates with efficacy. The impact of CD33 polymorphism on efficacy is also being researched. Watch for these results, which will hopefully allow for wiser utilization of this new agent in the future.
About Dr. Gamis
Alan S. Gamis, MD, MPH, is Chief of the Section of Oncology and Associate Division Director of Hematology, Oncology, and Bone Marrow Transplantation at Children's Mercy Hospital in Kansas City, Missouri. He is also a Professor of Pediatrics at the University of Missouri–Kansas City and an Adjunct Professor of Pediatrics at the University of Kansas Cancer Center. Dr. Gamis specializes in the treatment of pediatric patients with hematologic malignancies, including AML. He has served as a member of several clinical trial committees of the Children's Oncology Group, as well as several oversight committees, including serving as chairperson of the Myeloid Scientific Disease Committee and committee member of the Epidemiology Steering Committee and the Stem Cell Transplant Steering Committee. He was also a founding member and former chairperson of the Pediatric Blood and Marrow Transplant Consortium. Dr. Gamis's research focuses on strategies to improve outcomes in pediatric patients with AML. He has authored and coauthored numerous publications researching novel therapeutics for childhood cancers.
For More Information
Gamis AS, Alonzo TA, Meshinchi S, et al (2014). Gemtuzumab ozogamicin in children and adolescents with de novo acute myeloid leukemia improves event-free survival by reducing relapse risk: results from the randomized phase III Children's Oncology Group Trial AAML0531. J Clin Oncol, 32(27):3021-3032. DOI:10.1200/JCO.2014.55.3628
Lamba JK, Chauhan L, Shin M, et al (2017). CD33 splicing polymorphism determines gemtuzumab ozogamicin response in de novo acute myeloid leukemia: report from randomized phase III Children's Oncology Group trial. J Clin Oncol, 35(23):2674-2682. DOI:10.1200/JCO.2016.71.2513
Lambert J, Pautas C, Terré C, et al (2019). Gemtuzumab ozogamicin for de novo acute myeloid leukemia: final efficacy and safety updates from the open-label, phase III ALFA-0701 trial. Haemetologica, 104(1):113-119. DOI:10.3324/haematol.2018.188888
Pollard JA, Loken M, Gerbing RB, et al (2016). CD33 expression and its association with gemtuzumab ozogamicin response: results from the randomized phase III Children's Oncology Group trial AAML0531. J Clin Oncol, 34(7):747-755. DOI:10.1200/JCO.2015.62.6846
Short NJ, Richard-Carpentier G, Kanagal-Shamanna R, et al (2020). Impact of CD33 and ABCB1 single nucleotide polymorphisms in patients with acute myeloid leukemia and advanced myeloid malignancies treated with decitabine plus gemtuzumab ozogamicin. Am J Hematol. [Epub ahead of print] DOI:10.1002/ajh.25854
Transcript edited for clarity. Any views expressed above are the speaker's own and do not necessarily reflect those of i3 Health.