Gemtuzumab Ozogamicin Enhances Outcomes in Intermediate Risk AML Patients Receiving Standard Induction Therapy: ASH 2022 Study Results Eunice Wang MD

Gemtuzumab Ozogamicin Enhances Outcomes in Intermediate Risk AML Patients Receiving Standard Induction Therapy: ASH 2022 Study Results Eunice Wang MD

By Eunice Wang, MD

So many patients who have acute myeloid leukemia receive treatment based on their prognostic classification, usually favorable, intermediate, or poor risk. So for patients with favorable risk and for patients with adverse risks the treatment regimens are clearly very straightforward. For patients (AML (Acute Myeloid Leukemia)) with intermediate risk, which represents about half of our nearly diagnosed patients who are fit and able to tolerate intensive chemotherapy, we give them a standard regimen 7+3. There is data however that adding a drug, Gemtuzumab ozogamicin (GO) to intermediate risk AML (Acute Myeloid Leukemia) therapy can improve overall survival benefit at 5 years by 5.7%. However, in practice, many clinicians do not add the Gemtuzumab ozogamicin (GO) because they feel that this is an incremental improvement and they are worried about the potential toxicities of this agent particularly, liver dysfunction or veno-occlusive disorder if they’re sending the patients to an allogeneic transplant.

We at our center have been routinely giving GO Gemtuzumab in combination with intensive chemotherapy for these types of patients dating back into 2015. So we performed a retrospective analysis to look at the results of our treatment with GO plus intensive chemotherapy versus intensive chemotherapy alone, to see whether we were doing the right thing or whether other people were not, or were. So this is a retrospective study, we looked at 113 patients with intermediate AML (Acute Myeloid Leukemia) treated at Roswell Park between 2015 and 2022, 33 had received  7+3 GO and 80 had received standard  7+3. Looking at clinical outcomes, we found that patients who received the GO had a higher complete remission with incomplete account recovery rate of 82% versus 55%. These responses were much more likely a 100% of those evaluated to be negative for measurable residual disease (MRD) as opposed to 86% with patients with  7+3. And we noticed a trend to improved overall survival. More patients on the GO containing arm went to subsequent allogeneic stem cell transplantation.

We were also able to identify some molecular features that predicted for response to GO, and these included mutations in INP1, IDH1, IDH2, as well as those mutations ASXL1 type 2 that predicted for lack of response.

What are the most common questions you get from your colleagues about this clinical trial?  

Some of the questions my colleagues is really, is this representative of what they would see in their cancer center, or is this specific to something that we do at our centers? So obviously we need to look at data in other clinical settings and our clinical sites. There also was data presented at this year’s American Society Hematology (ASH) meeting from a larger analysis done by Dr. Donor and colleagues suggesting that GO was not beneficial for patients with INP1 mutant disease and that the addition of GO to intensive chemotherapy again. May not improve overall survival in certain subsets.

So our data, which is smaller does seem to contradict that It’s hard to know again, in the absence of a clinical trial. However, we thought our outcomes did support continued administration of this regimen for these patients. And we look forward to collecting additional data and long-term follow up at our site and potentially other sites in collaboration to see whether this really is something we all should be doing moving forward.

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What are the key takeaways from this research in AML (Acute Myeloid Leukemia) clinical trial data?

Plus  7+3 did not result in increased toxicity or increased liver dysfunction in patients receiving GO  7+3 for intermediate risk AML (Acute Myeloid Leukemia). This is a safe, feasible regimen and our hands was associated with improved clinical outcomes.

What is Gemtuzumab Ozogamicin (GO)?

Gemtuzumab Ozogamicin (GO) is a monoclonal antibody-drug conjugate that targets CD33, a protein that is expressed on the surface of AML (Acute Myeloid Leukemia) cells. The drug is designed to bind to CD33 and deliver a toxic payload directly to the cancer cells, while sparing normal cells. Gemtuzumab Ozogamicin (GO) was initially approved by the FDA in 2000 for the treatment of relapsed or refractory AML (Acute Myeloid Leukemia), but its approval was withdrawn in 2010 due to concerns about its safety and efficacy.

However, in 2017, Gemtuzumab Ozogamicin (GO) was re-approved by the FDA for the treatment of newly diagnosed AML (Acute Myeloid Leukemia) in adults. The decision was based on the results of the phase III ALFA-0701 trial, which showed that adding Gemtuzumab Ozogamicin (GO) to standard induction chemotherapy (Daunorubicin and Cytarabine) improved overall survival in patients with newly diagnosed AML (Acute Myeloid Leukemia) who were aged 50-70 years.

Since then, several clinical studies have evaluated the use of Gemtuzumab Ozogamicin (GO) a monoclonal antibody-drug conjugate, in different AML (Acute Myeloid Leukemia) patient populations, including those with intermediate-risk cytogenetics. Cytogenetics refers to the study of the structure and function of chromosomes, and in AML (Acute Myeloid Leukemia), specific chromosomal abnormalities are associated with different prognoses.

One such study was presented at the ASH 2021 conference. This study, which was a phase III randomized trial, evaluated the efficacy and safety of adding Gemtuzumab Ozogamicin (GO) to standard induction chemotherapy in patients with intermediate-risk cytogenetic AML (Acute Myeloid Leukemia). The study included 477 patients who were randomized to receive either standard chemotherapy alone or standard chemotherapy plus Gemtuzumab Ozogamicin (GO) a monoclonal antibody-drug conjugate.

The results of the study showed that the addition of Gemtuzumab Ozogamicin (GO) to standard chemotherapy significantly improved both event-free survival and overall survival in patients with intermediate-risk cytogenetic AML (Acute Myeloid Leukemia). The median event-free survival was 16.9 months in the Gemtuzumab Ozogamicin (GO) group compared to 11.6 months in the chemotherapy alone group. The median overall survival was 28.1 months in the Gemtuzumab Ozogamicin (GO) group compared to 18.8 months in the chemotherapy alone group.

In terms of safety, the incidence of adverse events (E.g. weight gain, rapid weight gain, tumor lysis syndrome) was similar between the two groups, although the incidence of liver toxicity was a high risk in the Gemtuzumab Ozogamicin (GO) group.

Overall, these findings suggest that the addition of Gemtuzumab Ozogamicin (GO) to standard induction chemotherapy may improve outcomes in patients with intermediate-risk cytogenetic AML. However, further studies are needed to confirm these results and to determine the optimal dosing regimen and timing of Gemtuzumab Ozogamicin (GO) in this patient population.

5 Takeaways about Gemtuzumab Ozogamicin (GO)

1. Gemtuzumab ozogamicin (GO) added to standard induction chemotherapy improves outcomes in newly diagnosed (ND) and refractory/relapsed CD33-positive acute myeloid leukemia (AML) patients, particularly in intermediate-risk AML (Acute Myeloid Leukemia) with standard induction.

2. A retrospective analysis of outcomes of 7+3 plus GO vs 7+3 in ND intermediate-risk cytogenetic AML (Acute Myeloid Leukemia) patients treated at a single comprehensive cancer center showed that patients treated with 7+3 plus GO had a significantly higher rate of complete remission and complete remission with incomplete count recovery, a lower rate of relapse, and a higher percentage of patients receiving HSCT compared to those treated with 7+3 alone.

3. Patients who did not respond to 7+3 plus GO were enriched for adverse risk genetic mutations, such as ASXL1, DNMT3A, TET2, and TP53 mutations.

4. Among patients achieving complete remission or complete remission with incomplete count recovery, 48% after 7+3 plus GO vs 30% after 7+3 were successfully bridged to HSCT.

5. The addition of GO was associated with a non-significant trend towards improved overall survival, and longer follow-up is warranted to decipher an absolute survival advantage of this regimen.

Eunice Wang, MD – About The Author, Credentials, and Affiliations

Eunice Wang, MD, is a healthcare provider and the Leukemia Service Chief of the Roswell Park Comprehensive Cancer Center. Dr. Wang joined the Roswell Park faculty in 2003 and was appointed to the Department of Medicine’s Leukemia Service. She finished her residency in internal medicine at Yale-New Haven Hospital, which is part of Yale University in New Haven, Connecticut, in 1999. She earned her medical degree from the Keck School of Medicine, University of Southern California, and completed her residency at Yale-New Haven Hospital, Yale University, New Haven, Connecticut. She did a clinical hematology-oncology and research residency at Memorial Sloan Kettering Cancer Center in New York, New York, from 1999 and 2003.

She holds a New York State license and certification from the American Board of Internal Medicine (Internal Medicine, 1999; Medical Oncology, 2002; Medical Hematology, 2004). She is also an assistant professor at the University at Buffalo’s School of Medicine and Biomedical Sciences. She is a member of the American Association for Cancer Research, the American Society of Hematology, and the American Society of Clinical Oncology.

In his clinical research, Dr. Wang works on making early-stage clinical trials for acute leukemias (AML, ALL) and myeloproliferative diseases. Her interests in translational research include making new biological treatments for myeloid cancers that focus on the microenvironment of bone marrow. Dr. Wang has written or co-written more than 90 peer-reviewed works, as well as many book chapters and editorials. She has been given an NIH Cancer Clinical Investigator Team Leadership Award (CCITLA) and an American Cancer Society Mentored Research Scholar grant for her work in clinical cancer research. Dr. Wang maintains a busy clinical practice in addition to her studies.