Correlation of CD33 expression level with disease characteristics and response to gemtuzumab ozogamicin containing chemotherapy in childhood AML
ABSTRACT CD33 is expressed on the majority of acute myeloid leukemia (AML) leukemic blasts and is the target for gemtuzumab ozogamicin (GO), a toxin-conjugated anti-CD33 mAb. In the present study, we quantified the CD33 mean fluorescent intensity of leukemic blasts prospectively in 619 de novo pediatric AML patients enrolled in Children's Oncology Group GO-containing clinical trials and determined its correlation with disease characteristics and clinical outcome. CD33 expression varied more than 2-log fold; a median mean fluorescent intensity of 129 (range, 3-1550.07) was observed. Patients were divided into 4 quartiles, quartiles 1-4 (Q1-4) based on expression and disease characteristics and clinical response defined across quartiles. High CD33 expression was associated with high-risk FLT3/ITD mutations (P < .001) and was inversely associated with low-risk disease (P < .001). Complete remission (CR) rates were similar, but patients in Q4 had significantly lower overall survival (57% ± 16% vs 77% ± 7%, P = .002) and disease-free survival from CR (44% ± 16% vs 62% ± 8%, P = .022). In a multivariate model, high CD33 expression remained a significant predictor of overall survival (P = .011) and disease-free survival (P = .038) from CR. Our findings suggest that CD33 expression is heterogeneous within de novo pediatric AML. High expression is associated with adverse disease features and is an independent predictor of inferior outcome. The correlation between CD33 expression and GO response is under investigation. These studies are registered at www.clinicaltrials.gov as NCT00070174 and NCT00372593.
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- "Approximately 80% of childhood AML cases express CD33, a glycosylated sialic acid-binding transmembrane receptor protein of the lectin family. High CD33 surface expression is associated with worse outcomes in children and adults with AML (9–12). The potent humanized anti-CD33 monoclonal antibody/calicheamicin conjugate gemtuzumab ozogamicin (GO) has been studied extensively in adults with AML, including APL. "
ABSTRACT: Approximately two-thirds of children with acute myeloid leukemia (AML) are cured with intensive multi-agent chemotherapy. However, refractory and relapsed AML remains a significant source of childhood cancer mortality, highlighting the need for new therapies. Further therapy intensification with traditional cytotoxic chemotherapy in pediatric AML is not feasible given the risks of both short-term and long-term organ dysfunction. Substantial emphasis has been placed upon the development of molecularly targeted therapeutic approaches for adults and children with high-risk subtypes of AML with the goal of improving remission induction and minimizing relapse. Several promising agents are currently in clinical testing or late preclinical development for AML, including monoclonal antibodies against leukemia cell surface proteins, kinase inhibitors, proteasome inhibitors, epigenetic agents, and chimeric antigen receptor engineered T cell immunotherapies. Many of these therapies have been specifically tested in children with relapsed/refractory AML in Phase 1 and 2 trials with a smaller number of new agents under Phase 3 evaluation for children with de novo AML. Although successful identification and implementation of new drugs for children with AML remain a formidable challenge, enthusiasm for novel molecular therapeutic approaches is great given the potential for significant clinical benefit for children who do not have other curative options.Frontiers in Oncology 03/2014; 4:55. DOI:10.3389/fonc.2014.00055
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- "Numerous antibodies to CD33 have been developed for clinical use, including gemtuzumab ozogamicin, a recombinant humanized anti-CD33 conjugated with calicheamicin (Hamann et al., 2002). This conjugate induced remission in relapsed AML, most cases being CD33+, but it also had some activity in CD33- cases probably due in large part to the calicheamicin effects (Jawad et al., 2010; Pollard et al., 2012). It was also able to eliminate promyelocytes in cases of acute promyelocytic leukemia. "
ABSTRACT: Unlike stem cells from solid tumors, the stem cells which initiate myelogenous leukemias arise in marrow, an organ with a unique circulation which allows ready access of leukemia cells, including leukemia stem cells (LSCs), to the vasculature. This poses unique problems in the targeting of LSCs since these cells are found circulating in the majority of leukemia cases at diagnosis and are usually not detectable during remission states. Because most cases of leukemia relapse, it is suggested that LSCs remain quiescent in the marrow until they eventually proliferate and circulate again. This indicates that effective targeting of LSCs must occur not only in peripheral circulation but in the micro-circulation of the marrow. Targeting such interactions may overcome cell adhesion-mediated treatment resistance, other multi-drug resistance mechanisms, and opportunities for clonal evolution in the marrow environment. Targeting selectins and integrins, signal transduction mediators, and chemokine/cytokine networks in the marrow micro-circulation may aid in abrogating leukemia-initiating stem cells which contribute to disease relapse. LSCs possess surface antigen profiles and signal transduction activation profiles which may allow differential targeting as compared with normal hematopoietic stem cells.Frontiers in Oncology 08/2012; 2:86. DOI:10.3389/fonc.2012.00086
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ABSTRACT: Although the identification of cancer stem cells as therapeutic targets is now actively being pursued in many human malignancies, the leukemic stem cells in acute myeloid leukemia (AML) are a paradigm of such a strategy. Heterogeneity of these cells was suggested by clonal analyses indicating the existence of both leukemias resulting from transformed multipotent CD33(-) stem cells as well others arising from, or predominantly involving, committed CD33(+) myeloid precursors. The latter leukemias, which may be associated with an intrinsically better prognosis, offer a particularly attractive target for stem cell-directed therapies. Targeting the CD33 differentiation antigen with gemtuzumab ozogamicin was the first attempt of such an approach. Emerging clinical data indicate that gemtuzumab ozogamicin is efficacious not only for acute promyelocytic leukemia but, in combination with conventional chemotherapy, also for other favorable- and intermediate-risk AMLs, providing the first proof-of-principle evidence for the validity of this strategy. Herein, we review studies on the nature of stem cells in AML, discuss clinical data on the effectiveness of CD33-directed therapy, and consider the mechanistic basis for success and failure in various AML subsets.Blood 01/2012; 119(26):6198-208. DOI:10.1182/blood-2011-11-325050 · 10.45 Impact Factor