Which are the most promising targets for minimal residual disease-directed therapy in acute myeloid leukemia prior to allogeneic stem cell transplant?

Ball, Brian; Stein, Eytan M.

doi:10.3324/haematol.2018.208587

Cited by 19 publications

(15 citation statements)

References 119 publications

(133 reference statements)

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“…MRD is an important prognostic factor for relapse and survival in AML and its eradication represents a key therapeutic strategy that may increase the number of AML patients with long-term survival [168]. At the moment, strategies that specifically target MRD are very limited [168]. Interestingly, CD123 represents a diagnostic biomarker of MRD and a potential therapeutic target for MRD eradication.…”

Section: Discussionmentioning

confidence: 99%

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CD123 as a Therapeutic Target in the Treatment of Hematological Malignancies

Testa

Pelosi

Castelli

2019

Cancers

113

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The interleukin-3 receptor alpha chain (IL-3Rα), more commonly referred to as CD123, is widely overexpressed in various hematological malignancies, including acute myeloid leukemia (AML), B-cell acute lymphoblastic leukemia, hairy cell leukemia, Hodgkin lymphoma and particularly, blastic plasmacytoid dendritic neoplasm (BPDCN). Importantly, CD123 is expressed at both the level of leukemic stem cells (LSCs) and more differentiated leukemic blasts, which makes CD123 an attractive therapeutic target. Various agents have been developed as drugs able to target CD123 on malignant leukemic cells and on the normal counterpart. Tagraxofusp (SL401, Stemline Therapeutics), a recombinant protein composed of a truncated diphtheria toxin payload fused to IL-3, was approved for use in patients with BPDCN in December of 2018 and showed some clinical activity in AML. Different monoclonal antibodies directed against CD123 are under evaluation as antileukemic drugs, showing promising results either for the treatment of AML minimal residual disease or of relapsing/refractory AML or BPDCN. Finally, recent studies are exploring T cell expressing CD123 chimeric antigen receptor-modified T-cells (CAR T) as a new immunotherapy for the treatment of refractory/relapsing AML and BPDCN. In December of 2018, MB-102 CD123 CAR T developed by Mustang Bio Inc. received the Orphan Drug Designation for the treatment of BPDCN. In conclusion, these recent studies strongly support CD123 as an important therapeutic target for the treatment of BPDCN, while a possible in the treatment of AML and other hematological malignancies will have to be evaluated by in the ongoing clinical studies.

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Section: Discussionmentioning

confidence: 99%

“…Interestingly, CD123 represents a diagnostic biomarker of MRD and a potential therapeutic target for MRD eradication. Some trials are specifically evaluating the impact of CD123 targeting on MDR eradication prior to allogeneic stem cell transplantation [168].…”

Section: Discussionmentioning

confidence: 99%

CD123 as a Therapeutic Target in the Treatment of Hematological Malignancies

Testa

Pelosi

Castelli

2019

Cancers

113

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“…These encouraging results of MRD monitoring in patients treated with GO gave rise to consider MRD as a surrogate endpoint for patient outcome. To date, several MRD-directed trials are currently investigating GO benefit [102].…”

Section: Prognostic Impact Of Minimal Residual Disease (Mrd)mentioning

confidence: 99%

Biomarkers of Gemtuzumab Ozogamicin Response for Acute Myeloid Leukemia Treatment

Fenwarth

Fournier

Cheok

et al. 2020

IJMS

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Gemtuzumab ozogamicin (GO, Mylotarg®) consists of a humanized CD33-targeted antibody-drug conjugated to a calicheamicin derivative. Growing evidence of GO efficacy in acute myeloid leukemia (AML), demonstrated by improved outcomes in CD33-positive AML patients across phase I to III clinical trials, led to the Food and Drug Administration (FDA) approval on 1 September 2017 in CD33-positive AML patients aged 2 years and older. Discrepancies in GO recipients outcome have raised significant efforts to characterize biomarkers predictive of GO response and have refined the subset of patients that may strongly benefit from GO. Among them, CD33 expression levels, favorable cytogenetics (t(8;21), inv(16)/t(16;16), t(15;17)) and molecular alterations, such as NPM1, FLT3-internal tandem duplications and other signaling mutations, represent well-known candidates. Additionally, in depth analyses including minimal residual disease monitoring, stemness expression (LSC17 score), mutations or single nucleotide polymorphisms in GO pathway genes (CD33, ABCB1) and molecular-derived scores, such as the recently set up CD33_PGx6_Score, represent promising markers to enhance GO response prediction and improve patient management.

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“…Such approaches depend on the knowledge of potential therapeutic targets in relapsed AML cells. [13][14][15].…”

Section: Introductionmentioning

confidence: 99%

The Progression of Acute Myeloid Leukemia from First Diagnosis to Chemoresistant Relapse: A Comparison of Proteomic and Phosphoproteomic Profiles

Aasebø

Berven

Hovland

et al. 2020

Cancers

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Acute myeloid leukemia (AML) is an aggressive hematological malignancy. Nearly 50% of the patients who receive the most intensive treatment develop chemoresistant leukemia relapse. Although the leukemogenic events leading to relapse seem to differ between patients (i.e., regrowth from a clone detected at first diagnosis, progression from the original leukemic or preleukemic stem cells), a common characteristic of relapsed AML is increased chemoresistance. The aim of the present study was to investigate at the proteomic level whether leukemic cells from relapsed patients present overlapping molecular mechanisms that contribute to this chemoresistance. We used liquid chromatography–tandem mass spectrometry (LC–MS/MS) to compare the proteomic and phosphoproteomic profiles of AML cells derived from seven patients at the time of first diagnosis and at first relapse. At the time of first relapse, AML cells were characterized by increased levels of proteins important for various mitochondrial functions, such as mitochondrial ribosomal subunit proteins (MRPL21, MRPS37) and proteins for RNA processing (DHX37, RNA helicase; RPP40, ribonuclease P component), DNA repair (ERCC3, DNA repair factor IIH helicase; GTF2F1, general transcription factor), and cyclin-dependent kinase (CDK) activity. The levels of several cytoskeletal proteins (MYH14/MYL6/MYL12A, myosin chains; VCL, vinculin) as well as of proteins involved in vesicular trafficking/secretion and cell adhesion (ITGAX, integrin alpha-X; CD36, platelet glycoprotein 4; SLC2A3, solute carrier family 2) were decreased in relapsed cells. Our study introduces new targetable proteins that might direct therapeutic strategies to decrease chemoresistance in relapsed AML.

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Which are the most promising targets for minimal residual disease-directed therapy in acute myeloid leukemia prior to allogeneic stem cell transplant?

Cited by 19 publications

References 119 publications

CD123 as a Therapeutic Target in the Treatment of Hematological Malignancies

CD123 as a Therapeutic Target in the Treatment of Hematological Malignancies

Biomarkers of Gemtuzumab Ozogamicin Response for Acute Myeloid Leukemia Treatment

The Progression of Acute Myeloid Leukemia from First Diagnosis to Chemoresistant Relapse: A Comparison of Proteomic and Phosphoproteomic Profiles

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