Expression CD33 is largely restricted to hematopoietic cells. [1] Because CD33 is consistently expressed on acute myeloid leukemia or AML blasts, it makes a promising target for ADC therapy.

Acute myeloid leukemia is an aggressive cancer which develops from precursor white blood cells, called blast cells, in the bone marrow. AML, primarily a cancer of the bone marrow and lymph nodes, is the second-most common form of leukemia in children, after acute lymphoblastic leukemia or ALL, and is characterized by overproduction and accumulation of immature white blood cells in the bone marrow, which crowd out healthy blood cells and cause anemia, bleeding, or infection. AML, which is also called acute nonlymphocytic leukemia it can affect both children and adults.

On of the possible therapies includes gemtuzumab ozogamicin (Mylotarg®; Pfizer/Wyeth-Ayerst Laboratories) is a recombinant, humanized anti-CD33 monoclonal antibody (IgG4 κ antibody hP67.6) covalently attached to the cytotoxic antitumor antibiotic calicheamicin (N-acetyl-γ-calicheamicin) via a bifunctional linker (4-(4-acetylphenoxy)butanoic acid). [2]  This drug has shown benefit in both adult and pediatric AML.  However, until recently, limited trial data was available about whether the response to gemtuzumab ozogamicin or GO directly correlates with CD33 expression level.

In an article published in the Journal of Clinical Oncology,  Jessica A. Pollard, MD, a pediatric hematologist/oncologist at Main Children’s Cancer Center, Scarborough, Maine, and affiliated with Seattle Children’s Hospital in Seattle, Washington and her co-workers investigated how the level of CD33 expression impacted the response to gemtuzumab ozogamicin in children with AML. [3]

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In the phase III AAML0531 Children’s Oncology Group Trial (NCT00372593),  supported by a St. Baldrick’s Career Development Award, the Children’s Oncology Group and the National Cancer Institute, Pollard and her team prospectively quantified CD33 mean fluorescent intensity (MFI) of leukemic blasts in 825 diagnostic specimens.  Based on CD33 expression, the researchers devided patients into four quartiles (Q1-Q4).   The values and the levels were then correlated with specific disease characteristics and outcome by treatment arm for the total study cohort and by cytogenetic/molecular disease risk-group.

Patients enrolled in the trial received a backbone of standard chemotherapy alone or in combination with gemtuzumab ozogamicin on day 6 of induction and day 7 of intensification.

Study rationale
Chemotherapeutic drugs stop the growth of cancer cells by killing cancer cells or by stopping them from dividing. In addition antibody-drug conjugates, such as gemtuzumab ozogamicin, block cancer growth by carrying a highly active anti-cancer killing agent directly to them.  A combination chemotherapy + gemtuzumab ozogamicin may, given the difference in MOA, kill more cancer cells.

With the start of the original randomized phase III trial, the researchers did not yet known whether the combination chemotherapy is more effective with or without gemtuzumab ozogamicin in treating young patients with newly diagnosed acute myeloid leukemia.  Hence, the purpose of the trial was to study the combination chemotherapy + gemtuzumab ozogamicin to see how well they work compared with combination chemotherapy alone.

Study results
According to the authors of the JCO article, their study is the first trial demonstrating that gemtuzumab ozogamicin, when added to conventional chemotherapy, lacks benefit in pediatric patients (Q1) with low CD33 expression (Relapse Risk [RR]: GO 36% vs. no GO 34%, P = .731; Event-free Survival [EFS]: GO 53% vs. no GO 58%, P = .456). However, authors also confirmed that in patients with high CD33 expression (Q2, 3 and 4), adding gemtuzumab ozogamicin to conventional chemotherapy was significantly linked to a reduction of relapse risk (GO 32% vs. no GO 49%, P < .001) and improved event free survival (GO 53% vs. no GO 41%, P = .005).

The authors explained that the differential effect shown was observed in all risk groups, including low-risk (LR), intermediate-risk (IR), and high-risk (HR) patients with low CD33 expression.  These patients  had similar outcomes regardless of exposure to GO. In contrast, the addition of GO to conventional chemotherapy resulted in a significant decrease in relapse risk and disease-free survival for patients with higher CD33 expression (LR Relapse Risk, GO 13% vs. no GO 35%, P = .001; LR disease-free survival, GO 79% vs. no GO 59%, P = .007; IR Relapse Risk, GO 44% vs. no GO 57%, P = .044; IR disease-free survival, GO 51% vs. no GO 40%, P = .078; HR Relapse Risk, GO 40% vs. no GO 73%, P = .016; HR disease-free survival, GO 47% vs. no GO 28%, P = .135).

The researchers conclude that the results of the original study may reflect gemtuzumab ozogamicin’s CD33-dependent MOA and the potential of more efficient targeting in a setting of high antigen expression. In addition, they believe that it is possible that a repeated exposure with gemtuzumab ozogamicin – in immediate-risk and low-risk patients – may, in case of high expression of CD33, result in a therapeutic benefit.

Other treatment options
Given the fact that in patients with high CD33 expression gemtuzumab ozogamicin shows a significant improvement in disease-free response in all risk groups, the study’s authors believe that there is a role for CD33-targeting therapeutics in subsets of pediatric AML-patients. However, due to the limited (commercial) availability of the drug, studies with novel CD33-targeting agents should be considered for the treatment of these patients.

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