Circulating tumor DNA to guide diagnosis and treatment of localized and locally advanced non-small cell lung cancer.

Liquid biopsy is a minimally invasive method for biomarkers detection in body fluids, particularly in blood, which offers an elevated and growing number of clinical applications in oncology. As a result of the improvement in the techniques for DNA analysis, above all next-generation sequencing (NGS) assays, circulating tumor DNA (ctDNA) has become the most informing tumor-derived material for most types of cancer, including non-small cell lung cancer (NSCLC). Although ctDNA concentration is higher in patients with advanced tumors, it can be detected even in patients with early-stage disease. Therefore, numerous clinical applications of ctDNA in the management of early-stage lung cancer are emerging, such as lung cancer screening, the identification of minimal residual disease (MRD), and the prediction of relapse before radiologic progression. Moreover, a high number of clinical trials are ongoing to better define the impact of ctDNA evaluation in this setting. Aim of this review is to offer a comprehensive overview of the most relevant implementations in using ctDNA for the management of early-stage lung cancer, addressing available data, technical aspects, limitations, and future perspectives.

Minimal residual disease monitoring via ctDNA: a case report of Lynch syndrome with synchronous colorectal cancer and review of literature.

Background: The investigation of circulating tumor DNA (ctDNA) as a substitute for minimal residual disease (MRD) has been a central focus in various clinical trials, with findings highlighting its effectiveness as a sensitive marker for detecting recurrence. In 2018, a joint review by the American Society of Clinical Oncology and the College of American Pathologists acknowledged a lack of current evidence guiding clinical decisions regarding ctDNA. Nevertheless, there are a multitude of ongoing studies exploring the future applications of ctDNA and its role in clinical decision making for select patient populations. Case Description: The case presented involves a patient with Lynch syndrome who developed synchronous left-sided colorectal cancers (CRC). Each primary malignancy exhibited a distinct mutational profile, introducing complexity to the personalized tumor-informed assays used for quantifying ctDNA levels. Initial ctDNA levels were negative until the assay was calibrated to the transverse colon primary tumor. Unfortunately, surveillance imaging showed radiographic recurrence coinciding with positive ctDNA findings. Treatment with the anti-PD-1 inhibitor pembrolizumab was initiated, resulting in the clearance of ctDNA after just four cycles. As of now, there is no radiographic or biologic evidence indicating disease recurrence. Conclusions: This case study sheds light on the evolving landscape and current limitations of ctDNA as a surrogate for MRD. We describe a patient with synchronous CRC who had radiographic recurrence and a negative MRD assay. Current tumor-informed assays are limited in their capacity to detect a single tumor, and by nature can miss both synchronous and metachronous malignancies. Assays tailored to multiple tumors or utilizing tumor agnostic methods should be a part of clinical decision making in this patient population.

[Clinical efficacy and safety of blinatumomab bridging CAR-T cell therapy in the treatment of patients with adult acute B-cell lymphoblastic leukemia].

Objective: Exploring the efficacy and safety of bridging blinatumomab (BiTE) in combination with chimeric antigen receptor T (CAR-T) cell therapy for the treatment of adult patients with acute B-cell lymphoblastic leukemia (B-ALL) . Methods: Clinical data from 36 adult B-ALL patients treated at the First Affiliated Hospital of Suzhou University from August 2018 to May 2023 were retrospectively analyzed. A total of 36 cases were included: 18 men and 18 women. The median age was 43.5 years (21-72 years). Moreover, 21 cases of Philadelphia chromosome-positive acute lymphoblastic leukemia were reported, and 16 of these cases were relapsed or refractory. Eighteen patients underwent blinatumomab bridging followed by CAR-T cell therapy, and 18 patients received CAR-T cell therapy. This study analyzed the efficacy and safety of treatment in two groups of patients. Results: In the BiTE bridge-to-CAR-T group, 16 patients achieved complete remission (CR) after BiTE immunotherapy, with a CR rate of 88.9%. One month after bridging CAR-T therapy, bone marrow examination showed a CR rate of 100.0%, and the minimal residual disease (MRD) negativity rate was higher than the nonbridging therapy group (94.4% vs. 61.1%, Fisher, P=0.041). The incidence of cytokine release syndrome and other adverse reactions in the BiTE bridge-to-CAR-T group was lower than that in the nonbridging therapy group (11.1% vs. 50.0%, Fisher, P=0.027). The follow-up reveals that 13 patients continued to maintain MRD negativity, and five patients experienced relapse 8.40 months (2.57-10.20 months) after treatment. Two of five patients with relapse achieved CR after receiving the second CAR-T cell therapy. In the nonbridging therapy group, 10 patients maintained continuous MRD negativity, 7 experienced relapse, and 6 died. The 1 year overall survival rate in the BiTE bridge-to-CAR-T group was higher than that in the nonbridging therapy group, with a statistically significant difference at the 0.1 level (88.9%±10.5% vs. 66.7%±10.9%, P=0.091) . Conclusion: BiTE bridging CAR-T cell therapy demonstrates excellent efficacy in adult B-ALL treatment, with a low recent recurrence rate and ongoing assessment of long-term efficacy during follow-up.

Decoding the Dynamics of Circulating Tumor DNA in Liquid Biopsies.

Circulating tumor DNA (ctDNA), a fragment of tumor DNA found in the bloodstream, has emerged as a revolutionary tool in cancer management. This review delves into the biology of ctDNA, examining release mechanisms, including necrosis, apoptosis, and active secretion, all of which offer information about the state and nature of the tumor. Comprehensive DNA profiling has been enabled by methods such as whole genome sequencing and methylation analysis. The low abundance of the ctDNA fraction makes alternative techniques, such as digital PCR and targeted next-generation exome sequencing, more valuable and accurate for mutation profiling and detection. There are numerous clinical applications for ctDNA analysis, including non-invasive liquid biopsies for minimal residual disease monitoring to detect cancer recurrence, personalized medicine by mutation profiling for targeted therapy identification, early cancer detection, and real-time evaluation of therapeutic response. Integrating ctDNA analysis into routine clinical practice creates promising avenues for successful and personalized cancer care, from diagnosis to treatment and follow-up.

Variant-specific BCR::ABL1 quantification discrepancy in chronic myeloid leukemia.

INTRODUCTION: Accurate quantification of the BCR::ABL1 fusion gene in whole blood is pivotal for the clinical management of chronic myeloid leukemia (CML) patients. The fusion protein encoded by BCR::ABL1 can vary in size, depending on the BCR and/or ABL1 gene breakpoint. The vast majority of CML patients have a p210 BCR::ABL1 fusion gene (M-BCR), which can be attributed to the presence of either e14a2 (b3a2) or e13a2 (b2a2) mRNA transcript junctions. METHODS: Twenty-five CML samples were analyzed in two different ISO15189-accredited centers that both use an Europe Against Cancer-based quantitative polymerase chain reaction (qPCR) protocol. Reanalysis of the sample set with transcript-specific standard curves and digital droplet PCR (ddPCR) were performed. RESULTS: qPCR quantification revealed a significant (up to 1 log) difference specifically for the e13a2 transcript variant in contrast to e14a2 transcripts (Hodges-Lehman 4.29; p < 0.001). Reanalysis of the sample set with transcript-specific standard curves abolishes the initial transcript-specific difference (Hodges-Lehman 0.003; p = 0.8192). Comparison of transcript-specific qPCR results of both centers with ddPCR, an absolute quantification method, showed a statically significant association, especially in the lower range, indicating the clinical utility of transcript-specific or absolute quantification methods. CONCLUSION: Our data show that differences between transcript-specific quantification might exist between centers, leading to potential clinical impact on the follow-up of CML patients. The use of transcript-specific standard curves for qPCR quantification, or absolute quantification, can significantly reduce these differences. Specific attention should be applied to the interpretation of quantification differences of CML patients that switch between diagnostic centers.

SWIGH-SCORE: A translational light-weight approach in computational detection of rearranged immunoglobulin heavy chain to be used in monoclonal lymphoproliferative disorders.

We present a lightweight tool for clonotyping and measurable residual disease (MRD) assessment in monoclonal lymphoproliferative disorders. It is a translational method that enables computational detection of rearranged immunoglobulin heavy chain gene sequences.•The swigh-score clonotyping tool emphasizes parallelization and applicability across sequencing platforms.•The algorithm is based on an adaptation of the Smith-Waterman algorithm for local alignment of reads generated by 2nd and 3rd generation of sequencers.For method validation, we demonstrate the targeted sequences of immunoglobulin heavy chain genes from diagnostic bone marrow using serial dilutions of CD138+ plasma cells from a patient with multiple myeloma. Sequencing libraries from diagnostic samples were prepared for the three sequencing platforms, Ion S5 (Thermo Fisher Scientific), MiSeq (Illumina), and MinION (Oxford Nanopore), using the LymphoTrack assay. Basic quality filtering was performed, and a Smith-Waterman-based swigh-score algorithm was developed in shell and C for clonotyping and MRD assessment using FASTQ data files. Performance is demonstrated across the three different sequencing platforms.

The role of minimal residual disease and serum free light chain ratio in the management of multiple myeloma.

Multiple myeloma (MM) denotes a cancerous growth characterized by abnormal proliferation of plasma cells. Growing evidence suggests that the complexity in addressing MM lies in the presence of minimal residual disease (MRD) within the body. MRD assessment is becoming increasingly important for risk assessment in patients with MM. Similarly, the levels of serum free protein light chain and their ratio play a crucial role in assessing the disease burden and changes in MM. In this paper, we review and explore the utilization of MRD and serum free light chain ratio in the treatment of MM, delving into their respective characteristics, advantages, disadvantages, and their interrelation.

Mutation and cell state compatibility is required and targetable in Ph+ acute lymphoblastic leukemia minimal residual disease.

Efforts to cure BCR::ABL1 B cell acute lymphoblastic leukemia (Ph+ ALL) solely through inhibition of ABL1 kinase activity have thus far been insufficient despite the availability of tyrosine kinase inhibitors (TKIs) with broad activity against resistance mutants. The mechanisms that drive persistence within minimal residual disease (MRD) remain poorly understood and therefore untargeted. Utilizing 13 patient-derived xenograft (PDX) models and clinical trial specimens of Ph+ ALL, we examined how genetic and transcriptional features co-evolve to drive progression during prolonged TKI response. Our work reveals a landscape of cooperative mutational and transcriptional escape mechanisms that differ from those causing resistance to first generation TKIs. By analyzing MRD during remission, we show that the same resistance mutation can either increase or decrease cellular fitness depending on transcriptional state. We further demonstrate that directly targeting transcriptional state-associated vulnerabilities at MRD can overcome BCR::ABL1 independence, suggesting a new paradigm for rationally eradicating MRD prior to relapse. Finally, we illustrate how cell mass measurements of leukemia cells can be used to rapidly monitor dominant transcriptional features of Ph+ ALL to help rationally guide therapeutic selection from low-input samples.

Improvement of daratumumab- or elotuzumab-mediated NK cell activity by the bi-specific 4-1BB agonist, DARPin α-FAPx4-1BB: A preclinical study in multiple myeloma.

Multiple myeloma (MM) progression is closely dependent on cells in the bone marrow (BM) microenvironment, including fibroblasts (FBs) and immune cells. In their BM niche, MM cells adhere to FBs sustaining immune evasion, drug resistance and the undetectable endurance of tumor cells known as minimal residual disease (MRD). Here, we describe the novel bi-specific designed ankyrin repeat protein (DARPin) α-FAPx4-1BB (MP0310) with FAP-dependent 4-1BB agonistic activity. The α-FAPx4-1BB DARPin simultaneously binds to FAP and 4-1BB overexpressed by activated FBs and immune cells, respectively. Although flow cytometry analysis showed that T and NK cells from MM patients were not activated and did not express 4-1BB, stimulation with daratumumab or elotuzumab, monoclonal antibodies (mAbs) currently used for the treatment of MM, significantly upregulated 4-1BB both in vitro and in MM patients following mAb-based therapy. The mAb-induced 4-1BB overexpression allowed the engagement of α-FAPx4-1BB that acted as a bridge between FAP+FBs and 4-1BB+NK cells. Therefore, α-FAPx4-1BB enhanced both the adhesion of daratumumab-treated NK cells on FBs as well as their activation by improving release of CD107a and perforin, hence MM cell killing via antibody-mediated cell cytotoxicity (ADCC). Interestingly, α-FAPx4-1BB significantly potentiated daratumumab-mediated ADCC in the presence of FBs, suggesting that it may overcome the BM FBs' immunosuppressive effect. Overall, we speculate that treatment with α-FAPx4-1BB may represent a valuable strategy to improve mAb-induced NK cell activity fostering MRD negativity in MM patients through the eradication of latent MRD cells.

Comparing the HER2 Status of the Primary Tumor to That of Disseminated Tumor Cells in Early Breast Cancer.

Breast cancer remains a leading cause of cancer mortality in women globally. Despite advancements in systemic therapy, the risk of distant recurrence persists even after such treatment and may be linked to disseminated tumor cells (DTCs). Variability in molecular characteristics between primary tumors (PTs) and distant metastases underscores the need to comprehensively understand metastatic pathways. This retrospective study investigated discrepancies between HER2 expression in PTs and DTCs and their implications for survival outcomes in 201 early breast cancer (EBC) patients. We found a significant association between HER2 expression in PTs and DTCs when classifying tumors as HER2-high/low/negative. Patients whose HER2 status was discordant between PTs and DTCs exhibited worse distant disease-free survival than those with concordant status. Multivariate analysis confirmed the HER2 status of DTCs as an independent prognostic factor for distant DFS. These findings emphasize the importance of assessing HER2 expression in DTCs and its potential implications for tailored therapy strategies in EBC. Furthermore, prospective trials are needed to validate these findings and explore targeted therapies based on the molecular characteristics of DTCs.

Association of the immediate perioperative dynamics of circulating DNA levels and neutrophil extracellular traps formation in cancer patients.

Objectives: Elevated circulating DNA (cirDNA) concentrations were found to be associated with trauma or tissue damage which suggests involvement of inflammation or cell death in post-operative cirDNA release. We carried out the first prospective, multicenter study of the dynamics of cirDNA and neutrophil extracellular trap (NETs) markers during the perioperative period from 24 h before surgery up to 72 h after curative surgery in cancer patients. Methods: We examined the plasma levels of two NETs protein markers [myeloperoxidase (MPO) and neutrophil elastase (NE)], as well as levels of cirDNA of nuclear (cir-nDNA) and mitochondrial (cir-mtDNA) origin in 29 colon, prostate, and breast cancer patients and in 114 healthy individuals (HI). Results: The synergistic analytical information provided by these markers revealed that: (i) NETs formation contributes to post-surgery conditions; (ii) post-surgery cir-nDNA levels were highly associated with NE and MPO in colon cancer [r = 0.60 (P < 0.001) and r = 0.53 (P < 0.01), respectively], but not in prostate and breast cancer; (iii) each tumor type shows a specific pattern of cir-nDNA and NETs marker dynamics, but overall the pre- and post-surgery median values of cir-nDNA, NE, and MPO were significantly higher in cancer patients than in HI. Conclusion: Taken as a whole, our work reveals the association of NETs formation with the elevated cir-nDNA release during a cancer patient's perioperative period, depending on surgical procedure or cancer type. By contrast, cir-mtDNA is poorly associated with NETs formation in the studied perioperative period, which would appear to indicate a different mechanism of release or suggest mitochondrial dysfunction.

Circulating Tumor DNA as a Complementary Prognostic Biomarker during CAR-T Therapy in B-Cell Non-Hodgkin Lymphomas.

The emergence of CD19-directed chimeric antigen receptor T-cell (CAR-T) therapy has revolutionized the treatment paradigm for R/R B-cell NHLs. However, challenges persist in accurately evaluating treatment response and detecting early relapse, necessitating the exploration of novel biomarkers. Circulating tumor DNA (ctDNA) via liquid biopsy is a non-invasive tool for monitoring therapy efficacy and predicting treatment outcomes in B-NHL following CAR-T therapy. By overcoming the limitations of conventional imaging modalities, ctDNA assessments offer valuable insights into response dynamics, molecular mechanisms of resistance, and early detection of molecular relapse. Integration of ctDNA monitoring into clinical practice holds promise for personalized therapeutic strategies, guiding the development of novel targeted therapies, and enhancing patient outcomes. However, standardization of assay methodologies and consensus on clinical response metrics are imperative to unlock the full potential of ctDNA in the management of B-NHL. Prospective validation of ctDNA in clinical trials is necessary to establish its role as a complementary decision aid.

MRD dynamics during maintenance therapy in 259 patients with nontransplant eligible multiple myeloma.

This study explored the impact of different maintenance therapies on survival outcomes in patients with multiple myeloma (MM), focusing on changes in minimal residual disease (MRD) during maintenance. Conducted at a single center, this retrospective study included 259 newly diagnosed MM patients who did not undergo autologous stem cell transplantation (ASCT). The results indicated that patients receiving lenalidomide as maintenance therapy showed significantly better progression-free survival (PFS) and overall survival (OS) compared to those treated with bortezomib or no maintenance therapy. However, bortezomib proved more effective in high-risk MM cases. Patients who were MRD-negative prior to starting maintenance therapy had a better prognosis than MRD-positive patients. Notably, lenalidomide was the most effective regimen irrespective of MRD status. Patients maintaining or achieving MRD-negativity within the first year of lenalidomide treatment exhibited improved prognoses, confirming lenalidomide as the optimal maintenance choice.

Intracranial residual lesions following early intensification in a patient with T-cell acute lymphoblastic leukemia: a case report.

BACKGROUND: T-cell acute lymphoblastic leukemia (T-ALL) tends to involve central nervous system (CNS) infiltration at diagnosis. However, cases of residual CNS lesions detected at the end of induction and post early intensification have not been recorded in patients with T-ALL. Also, the ratio and prognosis of patients with residual intracranial lesions have not been defined. CASE PRESENTATION: A 9-year-old boy with T-ALL had multiple intracranial tumors, which were still detected post early intensification. To investigate residual CNS lesions, we used 11C-methionine (MET)-positron emission tomography. Negative MET uptake in CNS lesions and excellent MRD status in bone marrow allowed continuing therapies without hematopoietic cell transplantation. CONCLUSIONS: In cases with residual lesions on imaging studies, treatment strategies should be considered by the systemic response, direct assessment of spinal fluid, along with further development of noninvasive imaging methods in CNS. Further retrospective or prospective studies are required to determine the prognosis and frequency of cases with residual intracranial lesions after induction therapy.

Survival after allogeneic transplantation according to pretransplant minimal residual disease and conditioning intensity in patients with acute myeloid leukemia.

Background: The measurement of minimal residual disease (MRD) by multiparametric flow cytometry (MFC) before hematopoietic stem cell transplantation (HSCT) in patients with acute myeloid leukemia (AML) is a powerful prognostic factor. The interaction of pretransplant MRD and the conditioning intensity has not yet been clarified. Objective: The aim of this study is to analyze the transplant outcomes of patients with AML who underwent HSCT in complete remission (CR), comparing patients with positive MRD (MRD+) and negative MRD (MRD-) before HSCT, and the interaction between conditioning intensity and pre-HSCT MRD. Study design: We retrospectively analyzed the transplant outcomes of 118 patients with AML who underwent HSCT in CR in a single institution, comparing patients with MRD+ and MRD- before HSCT using a cutoff of 0.1% on MFC, and the interaction between conditioning intensity and pre-HSCT MRD. Results: Patients with MRD+ before HSCT had a significantly worse 2-year (2y) event-free survival (EFS) (56.5% vs. 32.0%, p = 0.018) than MRD- patients, due to a higher cumulative incidence of relapse (CIR) at 2 years (49.0% vs. 18.0%, p = 0.002), with no differences in transplant-related mortality (TRM) (2y-TRM, 19.0% and 25.0%, respectively, p = 0.588). In the analysis stratified by conditioning intensity, in patients who received MAC, those with MRD- before HSCT had better EFS (p = 0.009) and overall survival (OS) (p = 0.070) due to lower CIR (p = 0.004) than MRD+ patients. On the other hand, the survival was similar in reduced intensity conditioning (RIC) patients regardless of the MRD status. Conclusions: Patients with MRD+ before HSCT have worse outcomes than MRD- patients. In patients who received MAC, MRD- patients have better EFS and OS due to lower CIR than MRD+ patients, probably because they represent a more chemo-sensitive group. However, among RIC patients, results were similar regardless of the MRD status.

Distinct longitudinal patterns of urine tumor DNA in patients undergoing surveillance for bladder cancer.

Cystoscopy is the gold standard for surveillance of non-muscle invasive bladder cancer (NMIBC), but the procedure is invasive and has suboptimal accuracy. The aim of this study was to investigate the potential of analyzing urine samples for the presence of urine tumor DNA (utDNA) to replace cystoscopy for surveillance of bladder cancer recurrence. In this longitudinal, prospective, and observational study, 47 patients were followed for recurrence for 2 years, involving analysis of utDNA using the BladMetrix DNA methylation biomarker test at each cystoscopy. In total, utDNA was detected in 21/23 recurrences (91% sensitivity), including 5/5 T1, T2, and carcinoma in situ (CIS) tumors (100%) and 10/12 Ta tumors (83%), with < 1% false-negative test results. Importantly, utDNA analysis showed the potential to reduce the number of cystoscopies by 55%, benefitting 79% of the patients. Eleven of 23 recurrences (48%) were detected earlier with utDNA than with cystoscopy, and distinct patterns of residual utDNA post-surgery indicated minimal residual disease (MRD) or field effect in 6% and 15% of the patients, respectively. In conclusion, utDNA analysis shows high sensitivity to detect tumor recurrence, potential to reduce the number of cystoscopies, and promise to guide patient-specific surveillance regimens.

[The value of minimal residual disease and IKZF1 deletion for predicting prognosis in adult patients with B-cell acute lymphoblastic leukemia].

Objective: To reassess the prognostic value of minimal residual disease (MRD) and IKZF1 gene deletions in adults with B-cell acute lymphoblastic leukemia (B-ALL) who received pediatric-specific chemotherapy regimens during the Nanfang Hospital PDT-ALL-2016 trial. Methods: We retrospectively analyzed the prognosis of 149 adult patients with B-ALL who were admitted to Nanfang Hospital from January 2016 to September 2020. Prognostic factors were identified using Cox regression models. Results: The complete remission rate was 93.2% in 149 patients, with a 5-year overall survival (OS) rate of (54.3±5.0) % and a cumulative incidence of relapse (CIR) of (47.5±5.2) %. The Cox regression analysis revealed that MRD positivity at day 45 (MRD(3)) after induction therapy was independently associated with relapse risk (HR=2.535, 95%CI 1.122-5.728, P=0.025). Deletion of IKZF1 gene was independently associated with mortality risk (HR=1.869, 95%CI 1.034-3.379, P=0.039). Based on MRD(3) and IKZF1 gene status, we categorized adult patients with B-ALL into the low-risk (MRD(3)-negative and IKZF1 gene deletion-negative) and high-risk (MRD(3)-positive and/or IKZF1 gene wild type) groups. The 5-year OS and CIR rates were (45.5±6.0) % vs (69.4±8.6) % (P<0.001) and (61.6±8.3) % vs (25.5±6.5) % (P<0.001), respectively, in the high-risk and low-risk groups, respectively. The multivariate analysis showed that the high-risk group was an independent risk factor for OS (HR=3.937, 95%CI 1.975-7.850, P<0.001) and CIR (HR=4.037, 95%CI 2.095-7.778, P<0.001) . Conclusion: The combined use of MRD and IKZF1 gene in prognostic stratification can improve clinical outcome prediction in adult patients with B-ALL, helping to guide their treatment.

The Evolving Landscape of Flowcytometric Minimal Residual Disease Monitoring in B-Cell Precursor Acute Lymphoblastic Leukemia.

Detection of minimal residual disease (MRD) is a major independent prognostic marker in the clinical management of pediatric and adult B-cell precursor Acute Lymphoblastic Leukemia (BCP-ALL), and risk stratification nowadays heavily relies on MRD diagnostics. MRD can be detected using flow cytometry based on aberrant expression of markers (antigens) during malignant B-cell maturation. Recent advances highlight the significance of novel markers (e.g., CD58, CD81, CD304, CD73, CD66c, and CD123), improving MRD identification. Second and next-generation flow cytometry, such as the EuroFlow consortium's eight-color protocol, can achieve sensitivities down to 10-5 (comparable with the PCR-based method) if sufficient cells are acquired. The introduction of targeted therapies (especially those targeting CD19, such as blinatumomab or CAR-T19) introduces several challenges for flow cytometric MRD analysis, such as the occurrence of CD19-negative relapses. Therefore, innovative flow cytometry panels, including alternative B-cell markers (e.g., CD22 and CD24), have been designed. (Semi-)automated MRD assessment, employing machine learning algorithms and clustering tools, shows promise but does not yet allow robust and sensitive automated analysis of MRD. Future directions involve integrating artificial intelligence, further automation, and exploring multicolor spectral flow cytometry to standardize MRD assessment and enhance diagnostic and prognostic robustness of MRD diagnostics in BCP-ALL.

How I treat newly diagnosed acute lymphoblastic leukemia.

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.