Optimizing Molecular Minimal Residual Disease Analysis in Adult Acute Lymphoblastic Leukemia

Starza, Irene Della; Novi, Lucia Anna De; Elia, Loredana; Bellomarino, Vittorio; Beldinanzi, Marco; Soscia, Roberta; Cardinali, Deborah; Chiaretti, Sabina; Guarini, Anna; Foà, Robin

doi:10.3390/cancers15020374

Cited by 12 publications

(7 citation statements)

References 128 publications

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“…[14][15][16][17][18] The sensitivity level may further be increased by using digital droplet PCR or next-generation sequencing. 19 The latter allows for the detection of ALL subclones. However, these methods have not been sufficiently standardized in ALL and, therefore, cannot be recommended for routine evaluation of MRD.…”

Section: First-line Treatment Of Ph-all: Current Statusmentioning

confidence: 99%

How I treat newly diagnosed acute lymphoblastic leukemia

Giebel

2024

Clinical Hematology International

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Treatment algorithms differ for adult patients with Philadelphia-negative (Ph-) and Philadelphia-positive (Ph+) acute lymphoblastic leukemia (ALL). For Ph- ALL intensive induction-consolidation chemotherapy using “pediatric-inspired” protocols is a standard of care. Allogeneic hematopoietic cell transplantation (allo-HCT) from either an HLA-matched sibling, unrelated or haploidentical donor should be considered for patients with high estimated risk of relapse. Inadequate response at the level of measurable residual disease (MRD) is the strongest adverse prognostic factor. Patients with B-ALL and detectable MRD should be treated with blinatumomab. In the future, the use of blinatumomab and/or inotuzumab ozogamycin in addition to first-line chemotherapy may become a new standard of care reducing the role of allo-HCT. For patients with Ph+ ALL, tyrosine kinase inhibitors (TKI) are the most important components of treatment protocols, while the intensity of chemotherapy may be reduced. Allo-HCT is recommended for all patients treated with imatinib along with low-intensity chemotherapy. Results of phase-II studies using front-line dasatinib or ponatinib in sequence or in combination with blinatumomab are very promising. Such a strategy may allow the avoidance of systemic chemotherapy. The future role of allo-HCT in this context appears uncertain.

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Section: First-line Treatment Of Ph-all: Current Statusmentioning

confidence: 99%

How I treat newly diagnosed acute lymphoblastic leukemia

Giebel

2024

Clinical Hematology International

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“…ddPCR uses thousands of droplets, each containing a single-DNA molecule to partition the sample and amplify the target DNA. This method has high precision and accuracy compared to other methods [163][164][165] and can be used to measure MRD for a variety of targets in acute leukemias and MDS [166][167][168][169]. ddPCR is a relatively new method, and its clinical utility for MRD measurement is still being evaluated.…”

Section: Can Provide Additional Genetic Informationmentioning

confidence: 99%

Novel precision medicine approaches and treatment strategies in hematological malignancies

et al. 2023

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Genetic testing has been applied for decades in clinical routine diagnostics of hematological malignancies to improve disease (sub)classification, prognostication, patient management, and survival. In recent classifications of hematological malignancies, disease subtypes are defined by key recurrent genetic alterations detected by conventional methods (i.e., cytogenetics, fluorescence in situ hybridization, and targeted sequencing). Hematological malignancies were also one of the first disease areas in which targeted therapies were introduced, the prime example being BCR::ABL1 inhibitors, followed by an increasing number of targeted inhibitors hitting the Achilles’ heel of each disease, resulting in a clear patient benefit. Owing to the technical advances in high‐throughput sequencing, we can now apply broad genomic tests, including comprehensive gene panels or whole‐genome and whole‐transcriptome sequencing, to identify clinically important diagnostic, prognostic, and predictive markers. In this review, we give examples of how precision diagnostics has been implemented to guide treatment selection and improve survival in myeloid (myelodysplastic syndromes and acute myeloid leukemia) and lymphoid malignancies (acute lymphoblastic leukemia, diffuse large B‐cell lymphoma, and chronic lymphocytic leukemia). We discuss the relevance and potential of monitoring measurable residual disease using ultra‐sensitive techniques to assess therapy response and detect early relapses. Finally, we bring up the promising avenue of functional precision medicine, combining ex vivo drug screening with various omics technologies, to provide novel treatment options for patients with advanced disease. Although we are only in the beginning of the field of precision hematology, we foresee rapid development with new types of diagnostics and treatment strategies becoming available to the benefit of our patients.

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“…Techniques for molecular monitoring of MRD such as quantitative PCR for both gDNA and RNA targets, digital droplet PCR for known hotspots in gDNA and next generation sequencing (NGS) MRD monitoring are evolving; however, they have still not been widely accepted [7,14,15]. Quantitative PCR (qPCR) KITs for routine diagnostics and MRD followup of fusion oncogenes expression and DNA point mutation/deletion/insertions are widely available and contain a serial of plasmid standards for quantification.…”

Section: Introductionmentioning

confidence: 99%

Standardization of Molecular MRD Levels in AML Using an Integral Vector Bearing ABL and the Mutation of Interest

Nachmias,

Krichevsky,

Gatt

et al. 2023

Cancers

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Quantitative PCR for specific mutation is being increasingly used in Acute Myeloid Leukemia (AML) to assess Measurable Residual Disease (MRD), allowing for more tailored clinical decisions. To date, standardized molecular MRD is limited to typical NPM1 mutations and core binding factor translocations, with clear prognostic and clinical implications. The monitoring of other identified mutations lacks standardization, limiting its use and incorporation in clinical trials. To overcome this problem, we designed a plasmid bearing both the sequence of the mutation of interest and the ABL reference gene. This allows the use of commercial standards for ABL to determine the MRD response in copy number. We provide technical aspects of this approach as well as our experience with 19 patients with atypical NPM1, RUNX1 and IDH1/2 mutations. In all cases, we demonstrate a correlation between response and copy number. We further demonstrate how copy number monitoring can modulate the clinical management. Taken together, we provide proof of concept of a novel yet simple tool, which allows in-house MRD monitoring for identified mutations, with ABL-based commercial standards. This approach would facilitate large multi-center studies assessing the clinical relevance of selected MRD monitoring.

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Optimizing Molecular Minimal Residual Disease Analysis in Adult Acute Lymphoblastic Leukemia

Cited by 12 publications

References 128 publications

How I treat newly diagnosed acute lymphoblastic leukemia

How I treat newly diagnosed acute lymphoblastic leukemia

Novel precision medicine approaches and treatment strategies in hematological malignancies

Standardization of Molecular MRD Levels in AML Using an Integral Vector Bearing ABL and the Mutation of Interest

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