Using FLT3 internal tandem duplication (FLT3/ITD) as a molecular marker, we tested the hypothesis that clinical outcome in AML correlates with disease involvement of CD34(+)/CD33(-) precursors.
In 2017, the US Food and Drug Administration approved four new treatments with indications for fms like tyrosine kinase 3 (FLT3)-mutated AML (midostaurin), newly diagnosed or relapsed/refractory CD33+AML (gemtuzumab ozogamicin), newly diagnosed therapy-related AML or AML with myelodysplasia-related changes (CPX-351) and relapsed/refractory AML with an isocitrate dehydrogenase (IDH)2 mutation (enasidenib).
We conducted a clinical trial to assess the feasibility and efficacy of CD33-directed chimeric antigen receptor-modified T cells (CART-33) for the treatment of refractory acute myeloid leukemia (AML).
In addition, blasts of patients with mutant nucleophosmin (NPM1) revealed significantly higher CD33 and CD123 expression pointing toward the possibility of minimal residual disease-guided interventions in mutated NPM1-positive AMLs.
Treatment with hypomethylating agent therapy might enhance anti-CD33 monoclonal antibody-mediated cytotoxicity against acute myeloid leukemia (AML) blasts through epigenetic effects on Syk and SHP-1 expression.
We evaluated gemtuzumab ozogamicin (CD33-targeted drug) used on a compassionate basis in patients diagnosed from 1995 until 2014 within Acute Myeloid Leukemia Berlin-Frankfurt-Münster studies, and identified 76 patients (<18 years) with highly-advanced and pre-treated AML [refractory <i>de novo</i> acute myeloid leukemia (n=10), <i>de novo</i> AML refractory to relapse (1<sup>st</sup> early: n=41; 1<sup>st</sup> late: n=10; 2<sup>nd</sup> or more: n=10), and secondary AML (n=5)].
Thus, this study confirmed the prognostic value of age and cytogenetic risk group and defined CD33 as a novel factor of independent prognostic importance in adult de novo AML.
From a consecutive series of 350 cases of adult de novo acute myeloid leukemia (AML), we identified 20 cases (6%) with a unique immunophenotype: CD33+, CD56+, CD11a+, CD13lo, CD15lo, CD34+/-, HLA-DR-, CD16-.
Together, these data suggest that SGN-CD33A has CD33-directed antitumor activity and support clinical testing of this novel therapeutic in patients with AML.
CD33, CD96 and Death Associated Protein Kinase (DAPK) Expression Are Associated with the Survival Rate and/or Response to the Chemotherapy in the Patients with Acute Myeloid Leukemia (AML).
Here we provide 'proof of concept' for retargeting of UniCAR T cells to CD33- and/or CD123-positive acute myeloid leukemia blasts in vitro and in vivo.
Taken singly, the sensitivity of these markers for AML with t(8;21) ranged between 39 and 100% with CD34+ having the highest and CD33- having the lowest and the positive predictive values (PPV) ranged between 5 and 21% with CD19+ having the highest and HLA-DR+ having the lowest.
To address whether multidrug resistance protein (MRP) affects GO susceptibility, we characterized Pgp, MRP1, and MRP2 expression in CD33+ cell lines and CD33+ AML samples and analyzed the effect of the Pgp inhibitor cyclosporine (CSA) and the MRP inhibitor MK-571 on GO-induced cytotoxicity.
We investigated whether a CD33/CD3-bispecific BiTE® antibody construct (AMG 330) with pre-clinical activity against AML-blasts by redirection of T-cells can eradicate CD33<sup>+</sup> MDSCs.
Gemtuzumab ozogamicin (Mylotarg; Pfizer, New York, NY) was the first antibody-drug conjugate to be approved for CD33-positive acute myeloid leukemia (AML).
Specifically, c-MYB (P </= 0.04) was significantly increased in ALL in the total fraction, whilst HOXA9 (P </= 0.19) and cystatin c (P </= 0.01) were increased in AML in the CD34(+) and CD34(-) fractions, respectively. c-MYB, hSNF2, RBAP48, HKRT-1, LYN, CD33, Adipsin and HOXA9 were increased in AML compared with remission AML, indicating an ability to determine disease activity.
We hypothesized that a leukemia-specific antigen could be created by deleting CD33 from normal hematopoietic stem and progenitor cells (HSPCs), thereby generating a hematopoietic system resistant to CD33-targeted therapy and enabling specific targeting of AML with CAR T cells.
To investigate the relationships between genetic variation and response to treatment in acute myeloid leukemia (AML), we genotyped 1931 variants on DMET genes in 94 CD33-positive AML patients enrolled in a phase III multicenter clinical trial combining Gemtuzumab-Ozogamicin (GO) with Fludarabine-Cytarabine-Idarubicin (FLAI) regimen, with the DMET Plus platform.
The most common (>30%) side effects of Mylotarg when used together with daunorubicin and cytarabine are hemorrhage and infection.The full indication is as follows: "Mylotarg is indicated for combination therapy with daunorubicin (DNR) and cytarabine (AraC) for the treatment of patients age 15 years and above with previously untreated, de novo CD33-positive acute myeloid leukemia (AML), except acute promyelocytic leukemia (APL).
Polo-like kinase inhibitor volasertib marginally enhances the efficacy of the novel Fc-engineered anti-CD33 antibody BI 836858 in acute myeloid leukemia.
However, outside of HSCT, only the anti-CD33 antibody drug conjugate gemtuzumab ozogamicin is currently approved as an antibody-targeted therapy for AML.