A Real-world Perspective of CD123 Expression in Acute Leukemia as Promising Biomarker to Predict Treatment Outcome in B-ALL and AML

Das, Nupur; Gupta, Ritu; Gupta, Sanjeev Kumar; Bakhshi, Sameer; Malhotra, Ankit; Rai, Sandeep; Singh, Saroj; Prajapati, Vijay Kumar; Sahoo, R.; Gogia, Ajay; Sharma, Atul; Kumar, Lalit

doi:10.1016/j.clml.2020.05.004

Cited by 22 publications

(19 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Using variable cutoffs of 5%, 10%, and 20%, Das et al. ( 34 ) reported the expression of CD123 in 75.6%, 66.2%, and 50% of AML. They also reported that CD123 expression at diagnosis was associated with post-induction MRD-positive status ( p = .001).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Leukemia Stem Cell Frequency at Diagnosis Correlates With Measurable/Minimal Residual Disease and Impacts Survival in Adult Acute Myeloid Leukemia

et al. 2022

View full text Add to dashboard Cite

Acute myeloid leukemia (AML) is a heterogenous disease in which the initiation and maintenance of the malignant clone is blamed on a rare population of leukemia stem cells (LSCs). The persistence of such a malignant population is referred to as measurable/minimal residual disease (MRD). Evaluation of MRD is the gold standard for follow-up of therapy and constitutes an independent prognostic parameter. As LSCs are the main contributor to the persistence of MRD, then MRD should correlate with the bulk of LSCs at the individual case level. MRD is measured at defined time points during therapy. However, LSCs can be evaluated at diagnosis, which ensures the advantage of early prediction of high-risk patients and allows for early therapeutic decisions. Using two simple four-color monoclonal antibody combinations (CD38/CD123/CD34/CD45 and CD90/CD133/CD45/CD33) and the prism function of the Coulter Navios flow cytometer, the frequency of LSC subsets was evaluated in 84 newly diagnosed adult AML patients. For each panel, 16 possible combinations were detected. Our results showed that there was extreme variability in the percentage of the LSC fraction between different cases, as well as at the individual case level. For each LSC subset, the median value was used to divide cases into low and high expressors. LSC subsets that showed an impact on overall survival (OS) and disease-free survival (DFS) included CD123+, CD 123+/CD34-, CD34-/CD38+/CD123+, CD34+/CD38-/CD123+, CD133+, and CD133+/CD33-. On multivariate analysis, only CD123 (p ≤ 0.001, SE = 0.266, HR = 2.8, 95% CI = 1.74.7) and CD133+/CD33- (p = 0.017, SE = 0.263, HR = 1.9, 95% CI = 1.1–3.1) retained their significance for OS. Likewise, only CD34+/CD38-/CD123+ (p ≤ 0.001, HR 2.3, SE: 0.499, 95% CI: 2.4–17.4) and CD133 (p = 0.015, HR 2.3, SE 0.34, 95% CI: 1.2–4.4) retained their statistical significance for DFS. The LSC frequency at diagnosis showed a moderate to strong correlation with MRD status at day 14 and day 28. In conclusion, the level of LSCs at diagnosis correlated with MRD status at day 14 and day 28 in AML patients and had a deleterious impact on OS and DFS. It may be used as an early marker for high-risk patients allowing for early therapeutic decisions.

show abstract

Section: Discussionmentioning

confidence: 99%

“…Several studies used LSC markers in parallel with standard MRD panels in a follow-up of AML ( 8 , 19 , 33 , 41 – 43 ). Two previous studies addressed the association of LSC frequency at diagnosis with MRD ( 28 , 34 ). However, they only tested one population (CD123+/CD34+ and CD123+, respectively).…”

Section: Discussionmentioning

confidence: 99%

Leukemia Stem Cell Frequency at Diagnosis Correlates With Measurable/Minimal Residual Disease and Impacts Survival in Adult Acute Myeloid Leukemia

et al. 2022

View full text Add to dashboard Cite

show abstract

“…Patients with high-risk disease and EOI MRD positivity were at higher risk of adverse events Das et al [23] 239…”

Section: All Patientsmentioning

confidence: 98%

“…Regarding the timings for assessment, five studies followed EOI assessments on days 29-33 [22][23][24][25][26], except for studies by Chatterjee et al [32] and Das et al [33] that made assessments between days 35 and 40 and 30 and 35, respectively [27]. Individual studies (n = 2) that evaluated at midinduction on day 21 or after phase 1a induction were also identified [27,28].…”

Section: Timing Of Mrd Assessmentmentioning

confidence: 99%

Minimal Residual Disease in the Management of B-Cell Acute Lymphoblastic Leukemia: A Systematic Review of Studies from Indian Settings

Menon

Singh²,

Bagal

et al. 2023

Indian J Hematol Blood Transfus

View full text Add to dashboard Cite

Minimal residual disease (MRD) has become an essential tool in the management of B-cell acute lymphoblastic leukemia (B-ALL) and aids in tailoring treatment strategies to suit specific patient needs. Although much progress has been made in this area, there is limited data on the use of MRD in the Indian context. Our objective was to identify relevant literature that discusses the utility of MRD in the management of B-cell ALL in adolescents and young adults (AYA) and adults in Indian settings. A systematic search and screening of articles were performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. The primary data source was PubMed followed by Google Scholar for articles and conference proceedings. Of the 254 records screened, 24 records were retained for analysis. MRD monitoring had a significant role in the management of AYA/adult B-cell ALL patients. Variability of results was observed across these studies with respect to methods, techniques, and use. However, these studies evidenced and validated the importance of MRD assessment in risk-adapted management of B-cell ALL and highlighted the need for optimization. The advances in MRD diagnostics and applications are yet to be tested and adopted in Indian settings. Hence, there is a need for in-depth research to develop and optimize approaches for calibrating country-specific management strategies. The potential role of MRD assessments in anticipating relapse or treatment failures warrants more attention for the preemptive positioning of novel strategies involving immunotherapies.

show abstract

“…CD123, the IL-3 receptor alpha chain, is highly expressed in AML as well as acute lymphoblastic leukemia (ALL) and has been associated with the LSC compartment. 1,[29][30][31] However, CD123 expression was also detected on normal tissues including hematopoietic progenitors [32][33][34][35] and endothelia. [36][37][38][39] Therefore, CD123-specific CAR-T applications are limited to strategies incorporating fine-tuned control mechanisms or may only be used for bridging to allo-HCT.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of switch-mediated costimulation in trans on universal CAR-T cells (UniCAR) targeting CD123-positive AML

et al. 2021

View full text Add to dashboard Cite

Chimeric antigen receptor T cells (CAR-T) targeting CD19 have achieved significant success in patients with B cell malignancies. To date, implementation of CAR-T in other indications remains challenging due to the lack of truly tumor-specific antigens as well as control of CAR-T activity in patients. CD123 is highly expressed in acute myeloid leukemia (AML) blasts including leukemia-initiating cells making it an attractive immunotherapeutic target. However, CD123 expression in normal hematopoietic progenitor cells and endothelia bears the risk of severe toxicities and may limit CAR-T applications lacking fine-tuned control mechanisms. Therefore, we recently developed a rapidly switchable universal CAR-T platform (UniCAR), in which CAR-T activity depends on the presence of a soluble adapter called targeting module (TM), and confirmed clinical proof-of-concept for targeting CD123 in AML with improved safety. As costimulation via 4-1BB ligand (4-1BBL) can enhance CAR-T expansion, persistence, and effector functions, a novel CD123-specific TM variant (TM123-4-1BBL) comprising trimeric single-chain 4-1BBL was developed for transient costimulation of UniCAR-T cells (UniCAR-T) at the leukemic site in trans. TM123-4-1BBL-directed UniCAR-T efficiently eradicated CD123-positive AML cells in vitro and in a CDX in vivo model. Moreover, additional costimulation via TM123-4-1BBL enabled enhanced expansion and persistence with a modulated UniCAR-T phenotype. In addition, the increased hydrodynamic volume of TM123-4-1BBL prolonged terminal plasma half-life and ensured a high total drug exposure in vivo. In conclusion, expanding the soluble adapter optionality for CD123-directed UniCAR-T maintains the platforms high anti-leukemic efficacy and immediate control mechanism for a flexible, safe, and individualized CAR-T therapy of AML patients.

show abstract

A Real-world Perspective of CD123 Expression in Acute Leukemia as Promising Biomarker to Predict Treatment Outcome in B-ALL and AML

Cited by 22 publications

References 37 publications

Leukemia Stem Cell Frequency at Diagnosis Correlates With Measurable/Minimal Residual Disease and Impacts Survival in Adult Acute Myeloid Leukemia

Leukemia Stem Cell Frequency at Diagnosis Correlates With Measurable/Minimal Residual Disease and Impacts Survival in Adult Acute Myeloid Leukemia

Minimal Residual Disease in the Management of B-Cell Acute Lymphoblastic Leukemia: A Systematic Review of Studies from Indian Settings

Evaluation of switch-mediated costimulation in trans on universal CAR-T cells (UniCAR) targeting CD123-positive AML

Contact Info

Product

Resources

About